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The Dooms laboratory focuses on understanding how autoreactive, islet-specific T cells, which are present in healthy people without causing harm, acquire their pathogenic functions and cause Type 1 Diabetes (T1D) when present in genetically susceptible individuals. The broad hypothesis is that faulty exposures and/or responses of T cells to microenvironmental factors such as cytokines and metabolites compromise immunoregulatory mechanisms and promote activation, differentiation and expansion of autoreactive T cells. The lab uses the non-obese diabetic (NOD) mouse model and patient samples to study this question in T1D. Currently, there are two active T1D projects in the lab: Mechanisms underlying the role of Interleukin-7 in T1D: Interleukin-7 (IL-7) is a cytokine with critical functions in many aspects of T cell biology, from early T cell development to mature T cell homeostasis and function (1). Evidence for a critical role of the IL-7/IL-7Rα axis in the pathogenesis of multiple autoimmune diseases, including T1D, is accumulating (1), and, as a result, clinical trials targeting IL-7Rα are underway. We first demonstrated that a monoclonal antibody blocking IL-7Rα prevented T1D development and reversed established disease in NOD mice by inhibiting memory T cells (2). Mechanistically, we showed that treatment with anti-IL-7Rα antibodies increased expression of co-inhibitory receptors such as PD-1, affecting T cell effector functions (3). Our current research efforts are centered around the hypothesis that aberrant IL-7 signaling due to genetic variations in signaling and/or increased exposure in the steady-state and at the inflammatory site promotes metabolic fitness and prevents exhaustion in diabetogenic T cells. In addition, we are interested in developing new strategies to utilize IL-7Rα blockade in combination with autoantigen vaccination for the treatment of T1D (4). The dietary fatty acid linoleic acid promotes pathogenic T cells in T1D: The incidence of T1D has globally been rising over the last 30 years, up to 5.3% annually in the United States, indicating that changing environmental conditions contribute to enhanced disease risk in genetically susceptible individuals. The nature of these environmental drivers, as well as the mechanisms by which they operate, remain largely undefined. The Western diet is one external factor that has emerged as a plausible candidate to promote autoimmune diseases, including T1D. One component of this diet that has garnered attention is the essential ω-6 polyunsaturated fatty acid linoleic acid (LA), which is present at increasingly high levels in the diet and has been associated with pro-inflammatory cytokine production. Our current research efforts are focused on our findings that exposure of autoreactive T cells to LA during activation changes their cytokine production profiles promoting a more diabetogenic phenotype. Thus, increasing levels of LA may promote the autoimmune response in T1D.

The Hamburg laboratory focuses on understanding the development and clinical relevance of vascular dysfunction in patients with type 2 diabetes and obesity. The lab uses translational research approaches that combine the measurement of vascular function in patients with characterization of endothelial phenotype at the cellular level to identify pathways that have potential to protect the vasculature from the accelerated aging induced by metabolic diseases. At present three projects are ongoing:

1) Mechanisms of endothelial dysfunction in patients with type 2 diabetes and obesity. Patients with type 2 diabetes experience accelerated vascular aging, premature atherosclerotic cardiovascular disease, and increased cardiovascular risk. Alterations in endothelial function promote atherosclerotic development in type 2 diabetes. We have identified signaling pathways that promote inflammation, oxidative stress and mitochondrial dysfunction in endothelial cells isolated from patients with type 2 diabetes. Using isolated endothelial cells, we have demonstrated several novel targets and therapies that may improve nitric oxide bioavailability. We have developed approaches to characterize coding and non-coding RNA in endothelial cells from patients with diabetes and are relating to measures of vascular aging to identify their functional relevance.

2) Mechanisms linking novel therapies for type 2 diabetes with vascular protection. Considerable enthusiasm exists for newer agents including GLP-1 agonists and SGLT2 inhibitors in reducing cardiovascular events in type 2 diabetes. Improvement of endothelial cell signaling and phenotype may serve as a marker for novel therapeutic interventions to improve cardiovascular health. We are conducting clinical intervention studies to evaluate whether novel diabetes medications will restore endothelial cell non-coding RNA expression and function.

3) ER stress and mitochondrial function in the obesity and diabetes. Metabolic stressors including elevated glucose and obesity impact endothelial cell metabolism characterized by ER stress and increased mitochondrial oxidative stress. We are evaluating the impact of therapies targeted at reducing ER stress and restoring mitochondrial health on vascular function in patients with diabetes.

Adipocytes, skeletal myocytes and some neurons express a specific isoform of the glucose transporter protein, Glut4. Under basal conditions this transporter is localized in intracellular membrane vesicles which fuse with the plasma membrane upon insulin administration. Translocation of Glut4 plays a major role in post-prandial glucose clearance and, more generally, in glucose sensing and metabolic homeostasis in the body. For a number of years, my lab has been involved in the dissection of the “Glut4 pathway” in various insulin-sensitive cells.

Another key physiological function of insulin is to inhibit lipolysis and to promote storage of triglycerides in fat tissue. We have discovered two novel pathways of regulation of lipolysis by insulin. One of these pathways is mediated by the insulin- and nutrient-sensitive mammalian Target of Rapamycin Complex 1, while the other is mediated by the transcription factor FoxO1. Currently, we are engaged in the dissection of both pathways at the molecular level.

Fat represents an important secretory tissue in the body. Unlike typical endocrine and exocrine cells, adipocytes produce and secret several physiologically important proteins, such as leptin, adiponectin, lipoprotein lipase, etc. and switch the secretory process from one protein to another in response to changing metabolic conditions. We are exploring connections between food intake, obesity and secretion of adipokines in order to understand the central role of fat tissue in the orchestrating the overall response of the organism to changing metabolic conditions.

The overarching theme in the Perissi Lab is dissecting the molecular mechanisms that control metabolic adaptation in response to nutrients availability, cell differentiation and oxidative stress. Current projects focus on two main areas:

1) Mechanisms regulating mitochondria-nuclear communication. We have recently identified a novel nuclear- mitochondrial communication pathway based on the translocation of a transcriptional cofactor, called G- Protein Pathway Suppressor 2 (GPS2), from the mitochondria to the nucleus to regulate the expression of nuclear-encoded mitochondrial genes. Our data indicate that GPS2-mediated retrograde signaling is critical for responding to acute mitochondrial stress by depolarization, and for sustaining mitochondrial biogenesis during adipocyte differentiation (Cardamone et al., Molecular Cell, 2018).
2) Dissecting the role of non-proteolytic K63 ubiquitination in the regulation of metabolic reprogramming. This stems from the identification of G-Protein Suppressor 2 (GPS2) as a specific inhibitor of the ubiquitin- conjugating enzyme Ubc13 (Lentucci et al., JBC, 2017). Investigating the role of the GPS2-Ubc13 module within different cellular compartments has led us to describe unexpected roles for GPS2 as a suppressor of PI3K/AKT signaling downstream of the insulin receptor and as an inhibitor of TLR and TNFR pro- inflammatory signaling pathways (Cardamone et al., Molecular Cell, 2012; Cederquist et al., Molecular Metabolism, 2016; Lentucci et al., JBC, 2017). Ongoing studies investigate novel targets of regulation, in addition to addressing the relevance and synergism among these functions in the context of obesity- associated inflammation/insulin resistance and breast cancer.

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