Members

A major research focus of the Arnaout Laboratory is to elucidate the structure and function of integrins, divalent cation-dependent cell adhesion receptors that play vital roles in normal cell physiology but also in common diseases. We use the information derived from our structural studies to design and test novel and safer anti- integrin drugs targeting inflammation, thrombosis, fibrosis, autoimmunity and cancer. The Laboratory uses cell, structure and molecular biology approaches and rodent and nonhuman primate (NHP) models for testing the generated compounds. Current projects are: 1. Integrins in proteinuric kidney disease. The stoichiometric cis association of the tetraspanin CD151 with podocyte integrin α3β1 is essential for stabilizing α3β1 in an active ligand binding conformation, thus maintaining the integrity of the glomerular filtration barrier (GFB). Other studies show that activation of αvβ3 in podocytes by inflammatory mediators, growth factors or mechanical/shear stress plays a critical role in disrupting the GFB. We are investigating the cellular, structural basis of the opposing roles α3β1 and αvβ3 play in regulating GFB homeostasis both in vitro and in rodent models of proteinuric kidney disease. inactivated genetically or pharmacologically in rodent models of proteinuric kidney disease. 2. Structural basis of platelet integrin αIIbβ3 activation and its therapeutic targeting. The paradigmatic platelet integrin αIIbβ3 plays a central non-redundant role in hemostasis but also in pathologic thrombosis. αIIbβ3 is normally kept in an inactive bent conformation on circulating platelets, but rapidly switches to an active (ligand-binding) conformation in response to inside-out signaling. The ligand-occupied receptor then transmits outside-in signals via the αβ transmembrane and cytoplasmic domains that initiate platelet adhesion, a response inadvertently produced by current drugs, leading to adverse outcomes, which has limited their clinical efficacy. The structural basis of bidirectional integrin signaling remains to be clarified. Ongoing studies are aimed at elucidating the structural basis of αIIbβ3 activation and developing compounds to avoid agonism while providing effective antagonism. 3. Role of integrin CD11b in delayed graft function (DGF). DGF is a manifestation of ischemia-reperfusion injury (IRI) in the transplanted kidney allograft. DGF is an important risk factor in T-cell or antibody- mediated biopsy-proven acute rejection, and the strongest risk factor for chronic allograft dysfunction exceeding even that of pre-transplant diabetes. We have shown that the archetypal innate immune receptor leukocyte integrin CD11b/CD18 mediates IRI in native NHP kidneys, and that a first-in-class anti- CD11b monoclonal antibody (mAb107) protected IRI native kidneys from otherwise irreversible kidney failure. We are evaluating the effect of limiting IRI with mAb107 on DGF in our well-studied NHP kidney transplant model. These studies have implications on preventing IRI of allogeneic pancreatic islets, a major cause of poor engraftment or progressive loss of allogeneic islet transplants in humans. 4. Abnormal metabolism in ADPKD. A hallmark of ADPKD cells is increased cell proliferation and aerobic glycolysis with upregulation of the glycolytic enzymes HK, PFK and PKM2 and down-regulation of LKB1/AMPK. Competitive inhibition of glycolysis with the non-metabolizable glucose analog 2-deoxy-D- glucose (DG) slowed disease progression in Pkd1 knockout mice. Yet the primary effector(s) that connects the underlying genetic defect in ADPKD to aberrant proliferation and Warburg metabolism remains to be identified. We now show that Warburg metabolism in the Pkd1 null mouse cells is β1 integrin-dependent and requires an extramitochondrial Plasma Membrane Electron Transport (PMET) redox system, which converts excess NADH back to NAD+ to fuel aerobic metabolism. We are evaluating the role of integrin β1 and PMET in energy utilization in tamoxifen-inducible mouse and human primary ADPKD cells, identify the β1 integrin signaling intermediates involved and the effect of PMET inhibition on rapid and slow kidney cyst growth in an inducible Pkd1 knockout mouse model.

The Babitt laboratory focuses on understanding the molecular underpinnings of iron homeostasis in health and disease. We previously discovered that the bone morphogenetic protein (BMP)-SMAD signaling pathway plays a crucial role in regulating systemic iron homeostasis by coordinating the regulation of the iron hormone hepcidin in the liver. Indeed, we previously determined that HJV (encoding hemojuvelin), the gene most commonly mutated in the severe juvenile onset form of the iron overload disorder hereditary hemochromatosis, is a BMP co-receptor, and that hemojuvelin-mediated BMP signals control hepcidin transcription in the liver. We also showed that BMP signaling pathway activators and inhibitors modulate hepcidin expression and systemic iron balance in vivo. More recently, we discovered that BMP6 and BMP2 are the main BMP ligands involved in hepcidin regulation and iron homeostasis, and that Bmp6 global or endothelial knockout (KO) mice and endothelial Bmp2 KO mice develop a similar iron overload phenotype as Hjv KO mice. Additionally, we demonstrated that the SMAD signaling pathway is not only critical for hepcidin regulation to control body iron balance, but also plays an independent protective role against tissue injury and fibrosis caused by iron excess.

Diabetes mellitus is a common complication of hemochromatosis and other iron overload disorders. Even in apparently healthy populations, increased dietary iron, especially heme iron, and high body iron stores, as measured by serum ferritin, are associated with an increased risk of type 2 diabetes mellitus and other insulin resistance states. A causative role for iron in the development of diabetes mellitus is supported by the fact that body iron reduction by phlebotomy or iron chelators improves glycemic control in these patients. Although the mechanisms by which iron contributes to the pathogenesis of diabetes and diabetic complications are not fully understood, oxidative stress induced by iron excess is thought to play a role. Evidence also suggests that the BMP signaling pathway itself plays a role in glucose homeostasis. For example, BMP9 has been proposed to play a role as a hepatic insulin sensitizing substance. Additionally, BMP ligands and the BMP receptors are expressed in pancreatic islet cells, and mice heterozygous for mutations in the BMP type I receptor ALK3 develop abnormal glucose metabolism with impaired insulin secretion.

A new focus in the laboratory is to use our novel genetic mouse models of impaired BMP signaling and hemochromatosis to explore the role of BMP-SMAD signaling and iron in islet cell physiology, pathology, and glucose metabolism.

Dennis Brown is Director of the MGH Program in Membrane Biology (PMB) within the MGH Division of Nephrology. The overarching goal of the Program is to understand how epithelial cells respond to physiological cues, including the antidiuretic hormone vasopressin, to regulate their function in the kidney and other organs. The group studies how the processes of exo- and endocytosis work together to regulate the cell surface expression of critical cell membrane proteins, including aquaporin water channels and proton pumping H+ATPases. These proteins are central to organ function and systemic body fluid and acid base homeostasis. The role of cytoskeletal proteins such as tubulin, actin and accessory proteins in this process is a focus, as well as clathrin-mediated endocytosis. The role of hormonally induced phosphorylation of aquaporin 2 and other trafficking proteins, and identification and regulation of the kinases and phosphatases that regulate protein trafficking and kidney function in response to vasopressin is a central theme.

The experimental systems used in the PMB cover a wide range, moving from dissecting protein-protein interactions at the molecular level, through in vitro cell systems expressing normal and mutated purified proteins, to whole animal models including transgenic and knockout mice. The aim is to understand the physiological and hormonal regulation of fluid and electrolyte homeostasis in the context of renal function and disease. Representative projects include: 1) discovering new drugs and strategies to correct defective vasopressin receptor signaling that leads to increased (diabetes insipidus) or decreased (hypertension) urine output in disease; 2) dissecting the pathways and proteins involved in the recycling of a vacuolar (V-type) H+ATPase to regulate acid-base secretion, urinary tract acidification and proximal tubule function; 3) a new project to understand the role of inflammation mediated by collecting duct intercalated cells in the pathogenesis of acute kidney injury (AKI).

The Das laboratory focuses on extracellular vesicles and their molecular cargoes as biomarkers in cardiovascular and metabolic diseases and seeks to determine their functional role in mediating phenotypes associated with cardiometabolic diseases including heart failure, atrial fibrillation, insulin resistance and MASLD. The laboratory uses a combination of human subject research including isolation of EVs from tissue explants, biofluids and organ-on-chip systems, combined with a variety of platforms to assess their molecular cargoes and functions. In addition, we have characterized novel murine models that allow for tracking of EVs to assess intercellular communication and the functional effects of EV targeting. Finally, as part of the Human Islet Research Network, we have projects defining beta-cell specific EVs to interrogate beta-cell stress, and investigate cross-talk between acinar cells, ductal cells and beta-cells in models of type 1 DM.

Lab website

My research program is focused on translating evidence-based nutrition and lifestyle interventions into real world clinical and community settings and understanding the psychological and behavioral factors that influence weight and activity outcomes. I have expertise in the design, implementation, and evaluation of lifestyle interventions that target weight loss and increased activity and the co-occurring problems of diabetes, prediabetes, hyperlipidemia, and hypertension. My 25+ years of clinical research experience has focused on understanding drivers of health and disease-specific quality-of-life in patients with hyperlipidemia, prediabetes, diabetes, and obesity including depression, distress, diet, and medication treatment, and to probe real-world barriers to effective care. I have designed and adapted lifestyle interventions that can promote clinically significant weight loss; improve diabetes self-management and prevent diabetes; and improve emotional well- being, quality of life and other health related outcomes in adults with diabetes, and prediabetes. My current translational intervention research in diabetes emphasizes sustainable, patient-centered approaches that have potential for wide dissemination. In Real Health-Diabetes, we are evaluating the reach, engagement, and cost- effectiveness of a lifestyle program delivered in-person or via telephone conference call (a scalable delivery format) compared with medical nutrition therapy. In Food is Medicine: a Randomized Clinical Trial of Medically Tailored Meals for Individuals with Type 2 diabetes Mellitus and Food Insecurity, we will evaluate the durability of effectiveness of a medically tailored meal intervention program that includes a lifestyle change component for individuals with type 2 diabetes on glycemic control, food insecurity, hypoglycemia, diabetes distress, diabetes self-efficacy and health-related quality of life compared with a food subsidy group. In Food as Medicine for HIV: A Randomized Trial of Medically Tailored Meals and Lifestyle Intervention, we will evaluate mechanisms whereby a food insecurity intervention may improve management of type 2 diabetes and examine the role of both nutritional improvement and health-related behavior change in doing so. The knowledge to be gained will help improve diabetes-related outcomes for patients with HIV and food insecurity.

My translational research is focused on bridging the gap between the clinical efficacy evidence base for nutrition and lifestyle intervention treatment efforts for diabetes and its implementation in real-world practice and community settings. My approach to lifestyle intervention for the treatment and prevention of diabetes is informed by behavioral science theory and empirical evidence, seeks multi-stakeholder input and collaboration and focuses on evaluating interventions that are scalable and have the potential for widespread dissemination.

As Director of the Immunobiology Laboratory at Massachusetts General Hospital (MGH), my research objective is to introduce new therapeutic concepts to treat autoimmune diseases and, more recently, cancer. I have been working in the fields of autoimmunity and immunology for nearly three decades, with a particular interest in identifying new biological processes that may be related to human disease and most frequently on the TNFR2 signaling pathway. The TNF receptor is center to Treg balance with overuse in cancer and underuse in autoimmunity. In the Immunobiology Lab, I lead teams that work to uncover the basic molecular and immunological mechanisms behind human and murine immune pathogenesis as it relates to TNF and translate these new innovations to the clinic. In various forms of autoimmunity (e.g., type 1 diabetes, Sjögren’s syndrome), we found that restoring tumor necrosis factor (TNF, TNFR2 signaling) can selectively eliminate pathogenic T cells and induce beneficial regulatory T cells (Tregs). Our findings have led to the establishment of global and collaborative clinical trial programs using repeat BCG vaccination, a known potent inducer of host TNF, in diverse autoimmune diseases including an effort to decrease the inflammation of Alzheimer’s. At MGH, this nearly century-old, safe and inexpensive vaccine is also being tested for other off-target effects such as for COVID-19 prevention. BCG vaccinations are also being tested in Italy in Phase III clinical trials in patients with multiple sclerosis. In 2015, we gained FDA approval for our protocol for Phase II testing of BCG vaccination in long-term diabetics and also established two new GMP/FDA approved manufacturing processes for BCG. In total, over 7 advanced trials are ongoing in the Immunobiology Labs. In 2018 we published the Phase I efficacy of repeat BCG vaccines in stably restoring blood sugars to the near normal range in long term diabetic subjects, a feat not feasible with insulin alone with safety. The pathway for tolerance induction in humans with TNF appears to be driven strongly by TNFR2 and now this is a target for both agonistic and antagonistic antibodies for the clinic.

Lab website

Our lab seeks to understand at the mechanistic level how atherosclerotic cardiovascular disease is driven by dysregulation of lipoprotein metabolism and inappropriate activation of innate immunity. The tools we used to investigate these questions include cellular models of macrophage biology, construction and analysis of mouse models of atherosclerosis, and bioassay development to interrogate clinical sample material from trials studying CVD risk in people living with HIV. We have made important contributions to these areas including one of the first descriptions of the role of the microRNA-33 in regulating ABCA1 expression and HDL biogenesis, and how diets high in fat and refined carbohydrates can trigger innate immune driven inflammation through a mechanism involving epigenetic remodeling and the activity of the NLRP3 inflammasome. To carryout aspects of this work we have extensively used the services of the MGH Cell Biology Core for our advanced imaging needs. We have also made use of Kahn-BIDMC Metabolic Physiology Core to obtain cellular and mouse model reagents.

The Florez lab aims to bring the treatment of diabetes and its complications into the new era of molecular medicine, using genetic and metabolomic approaches. To achieve these objectives, the lab undertakes the following set of activities:

1. Genetic discovery via high-throughput approaches. We have leveraged genome-wide association studies and whole-exome sequencing to discover genetic determinants of type 2 diabetes, related traits and downstream complications in diverse populations

2. Functional characterization of genetic association signals. Through fine-mapping and functional genomics we have begun to elucidate the molecular, cellular and physiological consequences of nucleotide changes in DNA sequence associated with type 2 diabetes in humans

3. Physiological assessment of glycemic and metabolic traits affected by genetic variation. In observational cohorts, clinical trials and dedicated physiological studies we have explored how type 2 diabetes- associated genetic variants impact glucose regulation in humans

4. Clinical translation of genetic findings. We have leveraged newly discovered genetic variation to understand the heterogeneity of type 2 diabetes, predict disease onset, or evaluate response to different treatment modalities

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Dr. Grinspoon is Chief of the Metabolism Unit and his research group focuses on understanding the metabolic consequences of abnormal fat distribution in lipodystrophy, and strategies to reduce ectopic adipose tissue and related inflammation. NAFLD is major consequence of dysfunctional adipose tissue and associated with insulin resistance and diabetes in lipodystrophy.

1) The group has shown reduced DICER in relationship to altered brown fat and metabolic regulation of adipose tissue and altered miRNA’a in this group. Of note the adipose DICER knockout demonstrated a lipodystrophic phenotype with severe insulin resistance, suggesting this pathway may be involved in regulating glucose regulation in lipodystrophy.

2) Dr. Grinspoon’s group has demonstrated reduced growth hormone pulsatility among lipodystrophic patients with excess visceral adipose tissue, strongly related to liver fat and has developed a novel hypothalamic peptide to augment endogenous GH pulsatility which was shown to reduce liver fat and visceral adiposity, while preventing liver fibrosis progression, in lipodystrophy, as well as selectively reducing VAT in generalized obesity. In Phase III trials for visceral adiposity, the therapy was associated with a 20% relative reduction in VAT vs. placebo and the larger the reduction in VAT, the lower the A1C, demonstrating the important relationship of this compartment to glucose control. Using banked tissue, the group has shown that IGF-I transcription is progressively reduced with advancing stages of liver disease, and is inversely related to glucose parameters, independent of circulating IGF-I, with implications for glucose control in NAFLD.

3) In a third set of studies, the group has shown that the renin angiotensin system is turned on in relationship to excess VAT ion lipodystrophy. Key studies investigating effects of RAAS blockade on this axis have shown reduced inflammatory proteins and reduced ectopic adipose tissue, but with a low BNP. Studies are ongoing to investigate effects of a dual strategy of blocking the RAAS with a neprilysin inhibitor to simultaneously augment BNP.

Marie-France Hivert, MD is an Associate Professor in the Department of Population Medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute. She is a clinical investigator with primary focus on the etiology and primordial prevention of obesity and related co-morbidities, particularly type 2 diabetes and gestational diabetes. Her interests also include fetal metabolic programming mechanisms and the integration of genetics, epigenetics, and environmental factors contributing to obesity and related disorders. She is currently involved in many international consortia investigating the genetics determinants of glycemic regulation during and outside of pregnancy.

Dr. Hivert is the PI of a prospective cohort called Genetics of Glucose regulation in Gestation and Growth (Gen3G). Gen3G research team recruited women in 1st trimester of pregnancy, collected biologic samples and detailed phenotypes during pregnancy (including oral glucose tolerance test) and at delivery. Gen3G research team completed follow-up mother-child pairs at 5 years post-birth, and is in the process of the 12 years old follow-up visit. Gen3G has a rich dataset of glycemic markers, adipokines, and anthropometric measures during and after pregnancy for the mothers and in offspring, in addition to genotypes and DNA methylation arrays in placenta and offspring blood (birth and 5y). Gen3G has also completed microRNA and RNA sequencing of placenta samples. This extensive multi-omics dataset allows investigations of determinants of glycemic regulation and pregnancy, as well as investigations of mechanisms linking maternal hyperglycemia and metabolic consequences in the offspring.

Dr. Hivert is also co-PI of Project Viva (PI = Oken) which is a prospective pre-birth cohort that was established between 1999-2002 and has been following up mothers and children throughout childhood and adolescence, collecting data and samples to investigate child health and common conditions (asthma, obesity, neurodevelopment, etc.). Project Viva research team is now following mother-child pairs >20 years post-birth. Project Viva also has an extensive amount of genotyping (mothers and children), epigenetics (cord blood, blood cells at 3yo and 8yo, blood and nasal cells at 12 yo), untargeted metabolomics (cord blood, blood at 8yo, 12yo, and 18yo), and longitudinal measures for many of their phenotypes. This allows many investigations from prenatal up to adolescence with a deep lifecourse approach.

Dr Hivert has been an active member of the genetic working group within the Diabetes Prevention Program. She has led many project and manuscripts help to understand the interaction between genetics and lifestyle in determinants of diabetes. Dr Hivert also continues to be an active member of multiple international consortia in the field of genetics and epigenetics of diabetes related traits (e.g. MAGIC, CHARGE), and early life determinants of adiposity and metabolic traits (e.g. EGG, PACE).

The Kaneki laboratory has been working on stress (e.g., burn injury)-induced insulin resistance, mitochondrial dysfunction and muscle wasting. In the attempt to clarify the underlying molecular mechanisms and help develop a clinical trial in burn patients, the lab uses genetically engineered mice, pharmacological approaches and cell culture system. In addition, the PI conducted a pilot clinical study of coenzyme Q10 in burn patients, based on the data in burned mice. At present, related to stress-induced insulin resistance and metabolic derangements the following project is ongoing:

Mechanisms by which burn injury induces insulin resistance and metabolic derangements. Metabolic derangements, including insulin resistance, mitochondrial dysfunction and hyperlactatemia, are a major complication of burn injury and negatively affect clinical outcomes of burn patients. However, the molecular mechanisms by which burn injury induces these metabolic derangements remain to be clarified. We have shown that: (1) burn injury increases farnesyltransferase expression and farnesylated proteins; and (2)

farnesyltransferase inhibitor (FTI) prevents burn-induced insulin resistance (which parallels reversal of increased basal [insulin-unstimulated] mTORC1 activation), mitochondrial dysfunction in mouse skeletal muscle and hyperlactatemia. We have also shown that burn injury induces the Warburg effect in mouse skeletal muscle, as indicated by increases in expression of hypoxia-inducible factor (HIF)-1α and its downstream glycolytic genes, which is prevented by FTI. Moreover, we have recently shown that FTI prevents sepsis-induced mitochondrial damage in mice. (Sepsis is a leading cause of mortality in burn patients.) In addition, we have reported that treatment with coenzyme Q10 prevents burn-induced metabolic aberrations (i.e., insulin resistance, mitochondrial dysfunction and hyperlactatemia) in mice. Based on these data, the PI conducted a pilot clinical study in burn patients (ClinicalTrials.gov Identifier: NCT02251626).

My research program is focused on the application of complex trait genetics to clinical practice. I am to rigorously test strategies for translating type 2 diabetes (T2D) and hemoglobin A1c (A1C) genetics to precision medicine in controlled, real-world research settings. I take genetic findings from largescale genome-wide association analyses of T2D and A1C to pharmacogenetic clinical studies involving detailed phenotyping and pharmacologic interventions, and patient-oriented outcomes research using biobanks and electronic health records. Ongoing research studies in my lab include 1) a study funded by the American Diabetes Association to examine host genetics underlying diabetes and COVID-19 severity (Principal Investigator), 2) a study funded by the American Diabetes Association to characterize the beta cell function and sulfonylurea response of individuals at the extremes of polygenic scores (Site Investigator), and 3) an examination of the association of genetics with A1C-glycemia mismatches funded by the Boston Area Diabetes Endocrinology Research Center (BADERC) Pilot and Feasibility Program and a Doris Duke Foundation Clinical Scientist Development Award (Principal Investigator). I play both leadership and participatory roles in genetic discovery efforts within national and international genetics consortia – Meta-Analysis of Glycemic and Insulin-related Traits Consortium (MAGIC), Trans-Omics for Precision Medicine (TOPMed) Program, Cohorts of Heart and Aging in Genomic Epidemiology (CHARGE) and the Million Veteran Program (MVP). Additionally, I have published studies on novel approaches to diabetes population screening using health administrative databases and population-based surveys, and on Mendelian randomization approaches to evaluate causal relationship between risk factors and cardiometabolic disease.

Dr. Meigs has been a practicing primary care general internist at MGH for over 30 years, during which time his lab has focused on the cause and prevention of type 2 diabetes and cardiovascular disease using biochemical, genetic epidemiology and health services translational research approaches. He is a senior leader of many major large international T2D genomics consortia, including MAGIC, DIAGRAM, AAGILE, CHARGE- and TOPMed-diabetes, NIDDK T2D AMP/CMD and the VA’s MVP cardiometabolic work group. Dr. Meigs is also an experienced research mentor of over 50 early career investigators, including nine K-award recipients.

Current projects include:
TOPMed Omics of T2D, Quantitative Traits: We aim to use whole genome sequence and blood omic biomarkers in the NHLBI Trans-Omics for Precision Medicine (TOPMed) study to illuminate the pathobiology of type 2 diabetes (T2D) and its quantitative traits fasting glucose, insulin and hemoglobin A1c. We will integrate TOPMed results with beta cell-, liver-, fat- and muscle-specific omics and epigenomic annotation in the Accelerating Medicine Partnership (AMP) T2D Diabetes epiGenome Atlas and with hundreds of additional genomic trait associations in the AMP T2D Knowledge Portal for ‘in silico variant-to-function’ and phenomic studies aimed to find new approaches to address the global epidemic of T2D.

TOPMed Omics of CVD in T2D : We aim to use blood omic biomarkers in the NHLBI TOPMed study to illuminate the pathobiology of cardiovascular disease (CVD) in T2D. T2D is driving a major global epidemic of CVD, where CVD events occur over twice as frequently in people with T2D as without. The reasons for this excess risk are unknown but likely involve perturbations across multiple omic dimensions, including whole genome sequence variation and whole blood methylation, transcription, proteomics and metabolomics, where individually and together they contribute to novel pathways to CVD in T2D.

eMERGE Phase IV Clinical Center at Mass General Brigham: The discovery and clinical use of polygenic risk scores (PRS) for complex traits promises to dramatically change the practice of medicine. Our eMERGE IV grant will leverage a large Biobank and a rich electronic medical record to define the clinical impact of PRS derived from diverse populations and the clinical impact of returning these results along with family history and clinical risk information to participants and their healthcare providers.

Development of Polygenic Risk Scores for Diabetes and Complications across the Life Span in Populations of Diverse Ancestry: T1D and T2D, gestational diabetes (GDM) and related complications are excellent disease models to study the utility of polygenic risk scores (PRS) for predicting heterogenous and complex health outcomes in a setting where dramatic racial/ethnic and socioeconomic disparities exist. To address the disparities in PRS across ancestries, we have assembled a multi-disciplinary team to aggregate and analyze the largest existing genetic data from more than 1.8 M individuals (35% non-European) with T1D, T2D, GDM and glycemia-related complications and quantitative traits to improve the PRS prediction of diabetes and progression across the lifespan in diverse ancestries. Accomplishing the aims of this proposal will demonstrate how genomic data can inform more efficient and targeted preventive strategies within healthcare systems and across ethnically diverse populations

The research program is aimed at utilizing the new tools of genomics and computational biology to understand mitochondrial biology and metabolism. We are particularly interested in the rare mitochondrial disorders – collectively the largest class of inborn errors of metabolism. Major efforts in the group are aimed at identifying all of the protein components of mitochondria, discovering the regulatory networks that control their expression and assembly, and discovering genetic variants that disrupt these proteins and networks in human disease. We have found that an elevated NADH/NAD+ ratio, or reductive stress, is an important driver of mitochondrial disease. Ongoing work is aimed at targeting this parameter. Some of our work has implications for type 2 diabetes.

The Mostoslavsky laboratory is interested in understanding the influence of chromatin on nuclear processes (gene transcription, DNA recombination and DNA repair) and the relationship between chromatin dynamics and the metabolic adaptation of cells. One of our interests is on the study of a group of proteins called SIRTs, the mammalian homologues of the yeast Sir2. Sir2 is a chromatin silencer that functions as an NAD-dependent histone deacetylase to inhibit DNA transcription and recombination. In the past few years, we have been exploring the crosstalk between epigenetics and metabolism. In particular, our work has focused on the mammalian Sir2 homologue, SIRT6. In recent years, we have identified SIRT6 as a key modulator of metabolism. Mice lacking SIRT6 exhibit severe metabolic defects, including hypoglycemia and hypoinsulinemia. SIRT6 appears to modulate glucose flux inside the cells, functioning as a histone H3K9 deacetylase to silence glycolytic genes acting as a co-repressor of Hif1alpha, in this way directing glucose away from to reduce intracellular ROS levels. This function appears critical for glucose homeostasis, as SIRT6 deficient animals die early in life from hypoglycemia. More importantly, SIRT6 acts as a tumor suppressor in colon cancer, regulating cancer metabolism through mechanisms that by-pass known oncogenic pathways.

Cancer cells prefer fermentation (i.e., lactate production) to respiration. Despite being described by biochemist and Nobel laureate Otto Warburg decades ago (i.e., the Warburg effect), the molecular mechanisms behind this metabolic switch remained unknown for decades. Our work identified SIRT6 as a critical modulator of the Warburg effect in both colon and skin cancer, providing a long-sought molecular explanation to this phenomenon. Further, our recent studies indicate that metabolism in cancer is a highly heterogeneous feature, with only a handful of cells (so called tumor propagating cells) adapted for glycolytic metabolism. We have also uncovered key roles for SIRT6 in DNA repair (anchoring the chromatin remodeler SNF2H to DNA breaks) and early development (acting as a repressor of pluripotent genes), indicating broad biological functions for this chromatin deacetylase. In addition, we identified SIRT6 as a robust tumor suppressor in pancreatic cancer, where it silences the oncofetal protein Lin28b, protecting against aggressive tumor phenotypes. As such, SIRT6 represents an example of a chromatin factor modulated by cancer cells to acquire “epigenetic plasticity”. Lastly, we more recently started expanding our research. We are exploring novel metabolic liabilities in cancer, including assessing the ability of cells to adapt to extreme nutrient conditions, and the unique epigenetic/metabolic adaptations of metastatic cells. On the other hand, we are looking into broader chromatin roles in DNA repair, using unique combinations of chromatin libraries and DNA repair assays where we can perform high throughput screenings.

Specific Projects:
1. Determining the role of SIRT6 in tumorigenesis using mouse models
2. Elucidating the role of histone modifications and chromatin dynamics in DNA repair
4. Determining molecular crosstalk between epigenetics and metabolism
5. Assessing metabolic liabilities in cancer and metastases.

Dr. Nathan directs the MGH Diabetes Center, which provides clinical care to patients with diabetes and focuses on the development and evaluation of innovative therapies for type 1 and type 2 diabetes and their complications. Dr. Nathan and the Diabetes Center have played a leadership role in the conduct of numerous NIH and Foundation supported multi-center trials that have defined modern-day diabetes prevention and treatment. These include: the Diabetes Control and Complications Trial (DCCT) and its ongoing follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, which demonstrated the primacy of intensive metabolic control in preventing the development of complications in Type 1 diabetes; the Diabetes Prevention Program (DPP) and DPP Outcomes Study (DPPOS) which established the means of preventing Type 2 diabetes; the Look AHEAD study which examined the role of a lifestyle intervention as a means of preventing heart disease in type 2 diabetes; the Immune Tolerance Network Study which explored islet transplantation as a treatment of type 1 diabetes; the TODAY study, exploring the treatments of type 2 diabetes in children and adolescents; the A1c-Derived Average Glucose Study (ADAG) which established the definitive translation of HbA1c into average glucose levels; and most recently GRADE, a comprehensive comparative effectiveness study of type 2 diabetes therapies. Dr. Nathan chairs (or chaired) DCCT/EDIC, DPP/DPPOS, ADAG and GRADE. Other current single center studies have promoted the translation of laboratory results into new therapies, such as the development of GLP-1 receptor agonist class of drugs and new techniques for islet transplantation, the development of an artificial pancreas for the treatment of type 1 diabetes, the immune basis of type 1 diabetes, cardiovascular disease prevention, and means of optimizing the care of type 2 diabetes by primary care practitioners. Epidemiological studies in collaboration with the Framingham Heart Study, Baltimore Longitudinal Study of Aging, and Nurses and Physicians Health Studies have explored the risk factors of diabetes and its complications and in particular the relationship between
glycemia and heart disease. A host of genetics and pharmacogenetic and quality improvement studies are also ongoing.

The Powe clinical research group focuses on studying diabetes and the glucose metabolism of women who are pregnant or recently postpartum. Studies aim to improve our understanding of metabolic disease affecting this population by focusing on endocrine physiology and genetics. Current studies focus on detailed longitudinal characterization of glycemic physiology in pregnancy and examining approaches to parse heterogeneity among women with gestational diabetes (GDM). We have defined physiologic subtypes of gestational diabetes and are investigating translation of our findings to personalize therapy for women with gestational diabetes. Selected projects include:

1) GO MOMs – Glycemic Observation and Metabolic Outcomes in Mothers and Offspring. GO MOMs is a multicenter prospective longitudinal study designed to characterize the glycemic profile of pregnancy using continuous glucose monitoring (CGM) technology in order to develop criteria using CGM measurements and/or early pregnancy oral glucose tolerance testing (OGTT) that are predictive, along with clinical factors, of adverse pregnancy outcomes in mothers and their newborns.
2) SPRING – Study of Pregnancy Regulation of Insulin and Glucose. SPRING aims to characterize pregnancy-associated changes in insulin secretion and sensitivity, compare insulin secretion and sensitivity in high-risk women who do and do not develop GDM, examine the contribution of maternal genetics to glycemic physiology, and discover proteins secreted by the placenta that affect glycemia.
3) HINT-GDM – Heterogeneity Informed Nutritional Therapy for Gestational Diabetes Mellitus. HINT-GDM aims to develop dietary interventions to minimize glycemic excursions in distinct physiologic subtypes of GDM and prospectively confirm previously observed associations between physiologically-defined GDM subtypes and hyperglycemia-associated adverse outcomes.
4) MHC – The MGH Maternal Health Cohort. The MHC is a large electronic medical record-based cohort that collects medical and health information from women seen for prenatal care at MGH to study the effects of chronic diseases on pregnancy outcomes and pregnancy’s impact on women’s health. Pregnancy is an understudied area, so this protocol aims to examine risk factors that affect maternal and neonatal outcomes which will help inform future interventions designed to improve women’s health. A subset of women in MHC provided blood samples during their pregnancy which are available for
5) MGH2 – The MGH Maternal Genetics and Health Study. MGH2 will add genetic data to the MHC cohort to examine genetic determinates of maternal and infant health. Initial work will focus on the genetics of GDM.

Leveraging the large patient population with cystic fibrosis (CF) cared for by the MGH CF Center, the goal of this research program is to improve our understanding and treatment of CF-related diabetes (CFRD). CF is a life-shortening disease that causes progressive respiratory decline. People with CF are also at high risk of developing CFRD, which not only worsens their health but also adds substantial treatment burden and compromised quality of life. Our research has investigated diabetes technologies in CF to (1) overturn age-old teachings on the accuracy of glycemic measures, (2) improve approaches to screening and diagnosis, (3) redefine nutrition and how we measure it, (4) explore the safety and efficacy of novel insulin delivery devices in this unique form of diabetes, and (5) improve access for patients to these technologies. This program has also supported the career development of multiple fellows and junior investigators who have gone on to successful careers in academic medicine and industry, and a key focus of our research group is providing mentorship in diabetes research.

With funding from the NIDDK and the Cystic Fibrosis Foundation (CFF), we are currently investigating the application of diabetes technology to the screening, diagnosis, and treatment of CFRD as well as the impact of nutrition on glycemic control and clinical outcomes. Utilizing resources from the clinical research core led by Dr. Nathan, we recently completed a clinical study investigating the use of continuous glucose monitoring (CGM) in the diagnosis of CFRD, finding that average glucose derived from CGM correlates well with A1c. We are also exploring the use of continuous glucose monitoring to the screening and diagnosis of CFRD. Funded by the NIDDK and Cystic Fibrosis Foundation, we are leading a multicenter randomized clinical trial investigating the safety and efficacy of artificial pancreas technology (the iLet bionic pancreas) in children and adults with CFRD. We are also leading the Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) CGM substudy, collecting comprehensive CGM data in pregnant women with CF throughout pregnancy at 30 CF Centers across the US, as well as the Strength and Muscle Related Outcomes for Nutrition and Lung Function in CF (STRONG-CF) investigating innovative measures of nutrition and sarcopenia in adults with CF at 25 CF Centers.

In addition to our focus on CFRD, we have also expanded our investigations to include other vulnerable and understudied diabetes populations, including pregnant women, those with insulin-requiring type 2 diabetes, and people with diabetes in rural regions who lack access to endocrinologists. In collaboration with BADERC investigator Dr. Camille Powe, we are planning clinical trials to adapt and investigate the safety and efficacy of the iLet bionic pancreas for the management of T1D and T2D during pregnancy, when tighter glycemic targets and dynamic insulin needs make management particularly challenging and high stakes. In addition, in collaboration with investigators in Family Medicine at the University of Colorado, we successfully completed a preliminary random-order clinical trial in 40 adults with T1D showing that the iLet bionic pancreas can be successfully deployed over telehealth in the primary care setting, and we now have funding from the Helmsley Charitable Trust to expand to a large multi-state randomized clinical trial enrolling people with type 1 and type 2 diabetes via telehealth in rural areas without endocrinology access, bringing this technology to under-served populations. We hope these studies will revolutionize how we care for our highest risk diabetes patients.

One of my lab’s major interests is the application of LC-MS based metabolomics to epidemiologic and physiologic studies of kidney disease, including diabetic nephropathy. We have spearheaded the first published studies of metabolomics to study the effects of the hemodialysis procedure, identify novel markers of death in end-stage renal disease, identify predictors of new onset CKD, and differentiate individuals with established CKD who do or do not progress. A key feature of these studies has been the integration of physiologic investigation—more specifically, collection of samples from the aorta and renal vein using invasive catheterization—to characterize how the human kidney modulates hundreds of molecules, providing insight on why select metabolites are deranged in renal failure. In parallel, my laboratory is interested in lipid metabolism in the kidney and beyond. In conjunction with Drs. Robert Gerszten (BIDMC) and Clary Clish (Broad Institute), we showed that lipid highly unsaturated fatty acid (HUFA) content can change rapidly, increasing in plasma triglycerides within 2 hours of various glycolytic stimuli, including oral glucose ingestion, sulfonylurea administration, and exercise. In follow up, we recently elucidated the biochemistry that underlies these human observations, identifying HUFA synthesis as a novel mechanism of glycolytic NAD+ recycling, analogous to lactate fermentation. The relevant desaturases are highly expressed in the kidney and liver, where their role in NAD+ recycling is acutely adaptive during acute stress, including acute kidney injury, but may contribute to dyslipidemia over time. In addition, these findings highlight a key biologic role for lipid desaturation independent of the HUFA end products and provide insight into genetic studies linking lipid desaturation with human disease, including diabetes.

Research in the Rosenzweig laboratory is focused identifying new mechanisms and targets in heart failure. Heart failure is closely related to metabolic dysregulation in general and diabetes in particular. In addition to studying what goes wrong in heart disease, a growing area of research has been identification of pathways that keep the heart healthy, using the exercised heart as a model. Earlier studies identified intracellular signaling pathways regulating cardiomyocyte survival and function, including the first demonstration that PI3- kinase and Akt1 are critical in this context. They are also important components in insulin signaling. Subsequent work went on to demonstrate novel targets amenable to pharmacological intervention in heart failure and arrhythmia, such as SGK1, the focus of a recently funded biotech company. Studies of how exercise benefits the heart showed that growth of the heart in response to exercise is fundamentally different from that in response to pathological stimuli such as pressure overload (Cell 2010). Moreover, exercise induces cardiomyogenesis in the adult mammalian heart (Nature Comm 2018). Comprehensive genome-wide analyses have identified candidate pathways that mediate the cardioprotective and regenerative effects of exercise (Cell Metabolism 2015; Circulation 2022). Ongoing efforts seek to exploit the translation potential of targeting these pathways.

My research laboratory focuses on discovery of genes and pathways underlying sleep and circadian rhythm disorders and investigates their mechanistic links with type 2 diabetes. We aim to chart a course from genetic discoveries to biological, physiologic, and clinical insights relevant to diagnosis and treatment of sleep disorders and related cardio-metabolic disease.

Illuminating the genetic and molecular basis of sleep and circadian rhythm traits and their link to cardio- metabolic disease. Our lab aims to understand the molecular basis of sleep and circadian rhythm behaviors and disorders by defining the genetic architecture, testing gene function in model organisms, and exploring shared biological pathways between these traits and cardio-metabolic disease. We have discovered hundreds of common genetic loci for morningness/eveningness preference, insomnia, sleep duration, daytime napping, and daytime sleepiness, and we find substantial heterogeneity and genetic overlap with neuropsychiatric and cardio-metabolic disease. Mendelian randomization studies suggest that insomnia contributes in a causal way to risk of type 2 diabetes. Our work has opened up novel lines of investigation and promises to yield important fundamental and translational insights and putative therapeutic targets for sleep and circadian disorders with relevance to multiple diseases.

Impact of Melatonin, MTNR1B diabetes risk gene and food timing on glucose tolerance. An estimated 5-12 million Americans use melatonin to treat sleeping problems and ~10% of working adults are shift-workers with increased diabetes risk, but the precise effect of melatonin, and its interaction with food intake on diabetes prevention and control is unknown. We found that variation in the melatonin receptor 1b gene (MTNR1B) and core clock gene cryptochrome 2 (CRY2) influence glycemic traits, implicating circadian rhythm pathways as important in glucose homeostasis and T2D. Our recent collaborative physiologic studies suggest that night eating at a time when melatonin levels are high impairs glucose tolerance, particularly in carriers of the MTNR1B risk allele. This may impact vulnerable populations of late-night eaters, shift workers or users of melatonin as a sleep-aid. We have ongoing follow-up genotype-targeted physiologic and in-vitro human pancreatic islet studies as well as epidemiologic studies to further explore mechanisms by which MTNR1B receptor variation increases risk of type 2 diabetes.

The Soukas laboratory focuses on identification and characterization of genetic pathways that promote healthy aging and reduce aging-associated metabolic diseases such as type 2 diabetes, obesity, and cancer. The lab uses a combination of genetic approaches in vertebrate and invertebrate model systems to determine how genetic pathways can be manipulated to have favorable effects on metabolism and aging. At present, three projects are ongoing:

1) Mechanisms by which metformin improves glucose and lipid homeostasis, prolongs lifespan, and blocks the growth of cancer. Metformin is the most commonly used medication for type 2 diabetes worldwide. In recent years, it has become clear that metformin also has anti-cancer properties and can prolong lifespan of model organisms. We recently published in Cell (PMC5390486) that metformin effects at mitochondria lead to alterations in nuclear transport, inactivating mTORC1, thereby, inhibiting cancer growth, and prolonging lifespan. Remarkably, this pathway is conserved from the invertebrate C. elegans to human.

2) Connecting starvation survival to obesity and type 2 diabetes. Starvation is among the most ancient of selection pressures. Starvation defenses activated when nutrients become scarce permit animals to survive until nutrients are plentiful again. We identified a thrifty genetic pathway that activates doubling to tripling of starvation survival when protein translation genes are inhibited. Turning off protein synthesis tripled fat stores and starvation survival while turning off proteasomal genes, which encode gene products that degrade proteins, led to very low body fat stores and tremendous shortening of starvation
survival. Surprisingly, the proteostasis machinery controls starvation survival by activating the master starvation regulator AMPK (Published in Cell Reports PMC5578715).

3) Manipulating insulin signaling to reduce aging-associated diseases and to promote healthy aging and healthy metabolism. Recent work in the aging field has shown that activation of autophagy, or “self-eating” is mechanistically required in almost every genetic, dietary, and pharmacologic manipulation that extends lifespan. Conversely, mutations in essential autophagy-related genes lead to human diseases such as diabetes, inflammatory bowel disease, and cancer. By studying the insulin-signaling component mTOR complex 2, we determine that it promotes health by reducing mitochondrial permeability. When mTOR complex 2 acts, it promotes mitochondrial health, permitting autophagy to have beneficial effects on longevity in invertebrates and to reduce ischemia-reperfusion injury in mTOR complex 2 signaling liver- specific knockout mice (published in Cell PMC6610881). This work has implications for metabolism, aging, heart attack, stroke, and organ transplantation. More recently, we have found that mTOR complex 2 has complicated roles in metabolism. Specifically, mTOR complex 2 promotes insulin resistance in animals fed a high fat diet by signaling through the downstream AGC family kinase Sgk1 (published in Cell Reports PMC8576737). As such inactivation of mTOR complex 2 has disparate effects on mitochondrial health and insulin resistance, so further work is dissecting how we can promote health by leveraging targets downstream of the kinase.

Our team’s research aims to identify molecular subtypes of type 2 diabetes in order to improve patient management. We interrogate genetic data across the spectrum from rare to common variation to identify novel diabetes genes and mechanisms of disease. At the rare end of the spectrum, we are part of a U54 through the NIDDK to better characterize atypical forms of diabetes using whole genome sequencing and physiological testing. At the common end of the spectrum, we are interested in leveraging the hundreds of common genetic variants identified through genome-wide association studies to identify pathways causing disease. We have employed variant-trait association clustering to identify pathways and developed pathway-specific polygenic scores to investigate how mechanistic pathways impact patient outcomes. Our research involves analyzing large-scale patient genomic data from the UK Biobank, the Mass General Brigham Biobank, and the Type 2 Diabetes Knowledge Portal. Our team participates in the ClinGen Monogenic Diabetes Expert Panel and studies the role of genetic testing in clinical practice and how to improve upon the current standard of care in endocrine clinical genetics.
References.

Deborah Wexler is the Associate Director of the BADERC and leads the Pilot and Feasibility Program. She is Chief of the Diabetes Unit at MGH and Associate Professor of Medicine at Harvard Medical School. Through her research and mentorship, Dr. Wexler aims to define and achieve optimal treatment, quality of care, and quality of life for people with type 2 diabetes using epidemiologic, clinical trial, and implementation science methodologies and through development and dissemination of guidelines and standards of care. Through her PCORI funded projects, she has also developed expertise in stakeholder engagement in research. She provides consultations on diabetes-related research in these and other areas as part of her BADERC role with special expertise in study design, recruitment/retention, practice-based research, clinical trial implementation, and stakeholder engagement.

Major past and current projects include:
1) GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) Study Role: MGH Site Principal Investigator; Member of the Executive Committee, and co-chair of the Outcomes Committee. This 37-site trial evaluated the long-term metabolic and clinical effects of four classes of glucose-lowering medications in combination with metformin for the treatment of type 2 diabetes. (https://grade.bsc.gwu.edu)
2) REAL HEALTH-Diabetes Study. This project adapted and implemented a medically supervised, evidence-based group lifestyle change program in usual care settings and found that it yielded clinically significant weight loss, whether delivered in-person or via telephone conference call groups, which increased reach without sacrificing efficacy.
3) Comparative effectiveness of diabetes medications in observational databases. Complementing her work on GRADE, Dr. Wexler has a long-standing collaboration with the PROMISE group of the Division of Pharmacoepidemiology at BWH (https://www.bwhpromise.org).
4) Evaluating the comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists in pragmatic comparative effectiveness trial funded by PCORI. Dr. Wexler is co-leader of the clinical coordinating center of PRECIDENTD (https://precidentd.org)

The overall goal in the laboratory is to discover and understand the functions of important mediators and effectors involved in innate and adaptive immunity. Of particular interest are cellular components and regulatory networks that interact dynamically within temporal, spatial, and pathophysiological contexts of immunity. We utilize integrative systems approaches that closely couple genome-wide experimentation with high-throughput assays and computational methods.

Using the gut as a model system, we identify immune mechanisms that are perturbed in inflammatory bowel diseases (IBD) and type 1 diabetes (T1D). Recent work has focused on generating systems-wide maps within the gut that capture immune features and metabolic states at single-cell resolution. First, we transcriptionally profiled tens of thousands of individual gut epithelial cells to chart distinct cell types and their intrinsic cell states and responses to infections. We uncovered new cellular markers and programs, associated sensory molecules with cell types, and further defined principles of gut homeostasis and pathogenesis. We further utilized this data to identify intestinal stem cell (ISC) subsets enriched for MHC class II (MHCII) machinery and demonstrated that key cytokines affected MHCII+ ISC renewal and differentiation in opposing ways to orchestrate tissue-wide responses: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. A separate single-cell study examined the human colon mucosa during health and ulcerative colitis (UC), revealing 51 epithelial, stromal, and immune cell subsets. We associated inflammatory fibroblasts with resistance to anti-TNF treatment and revealed that many UC risk genes are cell type-specific and co-regulated in relatively few modules, suggesting that a limited set of cell types and pathways underlie UC. Lastly, we developed two single-nucleus RNA-sequencing methods—RAISIN-seq and MIRACL-seq—to transcriptionally profile the rare and diverse cells of the enteric nervous system (ENS) in humans at high resolution. We uncovered several neuro-epithelial, neuro-stromal, and neuro-immune interactions as well as strong expression in enteric neurons of risk genes for neuropathic, inflammatory, and extra-intestinal diseases. Collectively, these studies expose a rewiring of intra- and inter-cellular circuitry during intestinal inflammation and contribute to a more comprehensive understanding of the interplay between human genetics and mucosal immunity during health and complex diseases.

We also determine the influences of the gut microbiome on health and disease using human cohorts and computational models. Analyzing microbial strain-level variation in a longitudinal cohort of children predisposed to T1D, we revealed functional consequences of strain diversity on early microbiome development and disease susceptibility. Using the same cohort, we characterized the natural history of the early microbiome in connection to T1D diagnosis, antibiotic treatments, and probiotics. In pursuit of molecular mechanisms underlying interactions between the microbiome and the immune system, we identify microbially-derived metabolites, such as indoleacrylic acid and sphingolipids, that promote intestinal epithelial barrier function and mitigate inflammatory responses. Our metagenomic and metabolomic analyses of IBD cohorts uncovered over 2,700 gut metabolites that were differentially abundant in IBD. Furthermore, we link enzymatic activities of gut microbes to host metabolism; we recently identified cholesterol dehydrogenases harbored by a clade of bacteria that associates with lower cholesterol levels in humans. To generate unique hypotheses regarding immune mechanisms, we also established an integrative platform—an antigen prediction model coupled with high-throughput validation—to define the immunodominance landscape of microbes across a broad range of immune pathologies and an algorithm that identified bacterial genomic regions mediating host adaptation and antibiotic resistance. Together, these studies contribute to a comprehensive understanding of the functional roles played by the microbiome in maintaining mucosal homeostasis and promoting immunological disorders.

The laboratory ultimately aims to translate human genetics to functional biology and pathway medicine. Leveraging insight gained from our functional studies, we use chemical biology to test therapeutic hypotheses and inform drug discovery programs.