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Insulin is the most powerful anabolic hormone in the body, transitioning it from the fasted to the fed state. The dysregulation of insulin signaling, or insulin resistance, plays a central role in the development of diabetes, cardiovascular disease and non-alcoholic fatty liver disease. In the liver, the gluconeogenic genes are key targets of insulin, and insulin suppression of the gluconeogenic genes is important for maintaining glucose homeostasis. However, numerous other targets exist. The mission of the Biddinger Lab is to define the other key targets of insulin and determine how they contribute to disease. We expect that our studies, by providing a more complete and granular understanding of insulin action, will lead to better therapies for insulin resistance and its sequelae. Lab website

The Flannick lab focuses on learning what large-scale genetic and genomic datasets can teach us about type 2 diabetes (T2D). We focus on techniques ranging from software engineering to statistical method development to genetic data analysis. Through these approaches, we hope to identify insights into diabetes only apparent once we combine the necessary datasets, develop the necessary methods, apply the necessary analyses, and present the necessary results in ways that any researcher can interpret. We have three major projects ongoing in the lab:

Rare coding variants and their contribution to T2D. Genome wide association studies (GWAS) of common variants are the dominant genetic study design for complex diseases like T2D. Complementary to these studies are whole exome sequence analyses, which allow us to directly implicate genes in T2D based on aggregate associations observed for the collection of rare coding variants within them. We aggregate and analyze whole exome sequence for T2D understand T2D’s genetic basis (Nature, PMC5034897), evaluate the extent to which rare coding variant associations exist throughout the genome (Nature, PMC6699738), and use rare coding variants to personalize diagnosis for T2D (Under review at Nature Genetics)

Methods to evaluate the contribution of a gene to T2D or related traits. Our work suggests that rare coding variant associations are present for many T2D-relevant genes, but they are too weak to detect with statistical significance for the foreseeable future. We develop statistical methods to model the probability that a gene is involved with T2D, given its observed rare coding variant and GWAS associations (Under review at Cell Metabolism). We are extending these methods to incorporate other non-genetic information as well as information from multiple traits to provide the best possible picture – given currently available genetic data – of if and how a gene is involved in T2D.

Disseminating the results of T2D genetic analyses to the world. Our group maintains the Type 2 Diabetes Knowledge Portal (T2DKP), which seeks to make genetic and genomic datasets for T2D and related traits more publicly accessible (Submitted to AJHG). The portal consists of a web-interface and underlying software platform that integrates numerous genomic datasets with bioinformatic methods for predicting relationships among diseases, variants, genes, and pathways. The T2DKP is the world’s clearinghouse for T2D-related genetic data and provides a foundation for numerous T2D-related genetic analyses.

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My laboratory is primarily interested in investigating how mammals acquire and utilize iron. In mammals, erythrocytes typically contain greater than 70% of the organism’s iron in the form of heme in hemoglobin. Over the past several years, many of the transporter and accessory proteins involved in intercellular iron metabolism have been described. However, many proteins involved in intracellular iron metabolism beyond the basic components of the transferrin cycle remain elusive. Furthermore, the enzymatic components of heme biosynthesis are well characterized, but accessory transporters and other proteins required to shuttle heme precursors between mitochondria and the cytoplasm are unknown. To investigate these areas, we are taking two general approaches. First, we are using modern genetic techniques to identify and characterize the genes underlying mouse and human hereditary defects in erythroid iron and heme metabolism that lead to congenital forms of anemia. Second, using targeted mutagenesis in the mouse, we are studying proteins implicated in systemic, intracellular, and erythroid iron homeostasis. In particular, we are interested in the pathogenesis in a group of bone marrow disorders known as sideroblastic anemias, in which erythroid precursors develop pathologic mitochondrial iron deposits. At present, we are working on three ongoing projects:

1) Congenital sideroblastic anemia (CSA): We have developed a growing repository of >250 CSA probands and are using positional cloning and next generation sequencing to define new disease genes. We have identified five novel disease genes and are now modeling these and other previously characterized phenotypes in mouse models.
2) In a multi-institutional collaborative RC2 grant we are systematically evaluating the genetics and genomics of inherited and acquired bone marrow failure disorders, including aplastic anemia, congenital cytopenias, and myelodysplastic syndromes in children.
3) The ubiquitin-proteasome system (UPS) in erythropoiesis: in collaboration with Dr. Dan Finley at Harvard Medical School, we are discovering the targets of UPS components in developing red blood cells.

I am a human geneticist and clinically active pediatric endocrinologist and have a long and successful track record in research. My group uses genetics to identify and understand the causal biology of polygenic diseases and traits. My main areas of focus relate to endocrinology, including two major unmet medical needs (obesity and diabetic kidney disease), height (the classical model polygenic trait), and metabolomics. Over the last decade, our work has provided multiple insights into the genetics of obesity and other polygenic traits, and provided early, compelling genetic evidence for two different signatures of recent human evolution/selection.

I have substantial expertise in human genetics and an extensive track record of productivity that has had an impact on the field. I was an early leader in shaping the design of genome-wide association studies (GWAS) showing that meta-analysis of genetic association studies with stringent statistical thresholds would be a successful route to robust genetic associations1,2. I organized and continue to lead the GIANT consortium, which has discovered nearly all the variants known to be associated with measures of obesity and height). I co- lead the GENIE consortium, which has discovered the common variants known to be associated with kidney disease in individuals with type 1 diabetes5,6.

We have developed computational methods that integrate multiple data types to translate genetic discoveries into new biologic insights. We have also developed methods that allow us to extend metabolomics to unknown signals from untargeted profiling data9 and have combined genetic and metabolomics data to study causal relationships with diet, obesity, and diabetes related outcomes. We are now performing genetic studies of rarer variation in large populations and individual families, including whole exome and whole genome sequencing, and studies of metabolite levels and their relationship to obesity. We are also engaged in functional follow up of genes and variants emerging from GWAS. My lab has discovered multiple new genes and rare variants that are responsible for single gene disorders related to pediatric endocrine phenotypes. I have mentored >25 trainees, with consistently successful publication records and career trajectories.

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A main focus of our lab is to investigate the correlation between systemic metabolism and cancer incidence and progression, with the goal of identifying metabolic dependencies that could be targeted therapeutically in cancer patients.

Using models of lung, pancreatic and other tissue cancers, our lab aims at understanding:
How tumors survive and thrive in nutrient-limiting environments
How tumor growth and metabolism can be affected by the systemic metabolic state of the host (e.g. dietary restriction, obesity, insulin resistance)
How the host systemic metabolic state can, itself, get affected by tumor growth and metabolism (e.g. cancer-associated cachexia, or energy-wasting syndrome)

In our most recent work, we describe the identification of a unique metabolic dependency in pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with no effective therapies. We find that PDA relies on de novo ornithine synthesis (DNS) from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis. We find that this dependence associates with arginine depletion in the PDA tumor microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

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The long-term interest of our laboratory is to bridge molecular, cellular, and system approaches to decipher the neuronal modulatory and circuitry mechanisms underlying diabetes and obesity. By leveraging and combining a battery of cutting-edge technologies, including genetically engineered mouse models, recombinant viral vectors and viral tracing system, optogenetic and pharmacogenetic approaches, patch-clamp electrophysiology, 2-photon laser scanning microscopy, and 2-photon laser uncaging methods (2PLSM/2PLU), we are interrogating the following questions: 1) how neurons in the central nervous system translate their intrinsic firing properties to the controlling of energy and glucose homeostasis, and what circuits are involved; 2) how metabolic signals, including circulating metabolites, hormones, and neuropeptides, act on circuit neurons, shape their firing outputs, and modulate related synaptic neurotransmission; and 3) what kinds of receptors, ion channels, or cellular signaling molecules are rooted to bear these physiological processes and how their dysfunctions contribute to the pathogenesis of diabetes and the related complications. Understanding these above questions will provide novel insights on the treatment and prevention of diabetes.

Our laboratory is interested in understanding how vascular networks are formed and the mechanisms by which vascular networks engraftment occurs upon transplantation. Every year, millions of grafting procedures are performed in the United States to replace damaged and/or diseased tissues, including pancreatic islets, skin, bones, nerves, blood vessels, and fat. The success of these procedures closely depends on achieving adequate revascularization of the grafts. However, inadequate revascularization remains a common outcome, leading to various degrees of graft resorption and failure. As a result, patients often require additional grafting, which imposes added donor site morbidity, operating room time, and cost. Moreover, repetitive grafting is limited by donor tissue availability. Thus, the search for new approaches to improve graft revascularization continues to be a pressing clinical need.
We specialize in the biology of human Endothelial Colony-Forming Cells (ECFCs). These ECFCs are progenitors of endothelial cells that circulate in cord blood and adult peripheral blood and have enormous potential in Regenerative Medicine because they can generate large amounts of autologous endothelial cells for vascular therapies. We also specialize in methods to bioengineer functional microvascular networks in vivo. Our approach combines human endothelial cells with human mesenchymal stem cells (MSCs) into a biocompatible hydrogel to form organized vascular networks that when implanted into immunodeficient mice join with the host vasculature. This model is ideally suited for studies on the cellular and molecular mechanisms of human vascular network formation and for developing strategies to improve microvascular engraftment in surgical grafting. In addition, our model allows us to study the mechanisms by which the endothelium modulates the activity of co-transplanted stem cells and to elucidate how tissue-specific endothelial cells influence the cross-talk that occurs between these stem cells and the vasculature.

In addition, an important part of our research relies on having high quality human pancreatic islets to study different strategies for vascularization and engraftment. For human islets, we worked with the Pancreatic Islet Isolation Core at the Massachusetts General Hospital. The service is provided through the Boston Area Diabetes Endocrinology Research Center (BADERC); this service has been exceptional and critical for our research progress. The islets we obtain through BADERC are of exceptional high quality as they are similar to those intended for transplantation and are isolated by standard clinical methods.

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