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  • Dr.  Danielle Melloul
Danielle Melloul
Research Interests
The research in the lab focuses on the molecular mechanisms involved in insulin producing β-cell function and survival under physiological and pathophysiological conditions. Since insulin is the main regulator of glucose homeostasis, the normal function of the β-cells is crucial for maintaining normal blood glucose levels in the organism. Diabetes mellitus is a heterogeneous group of disorders characterized by an excess in blood glucose levels or hyperglycemia.
Candidate Genes Affecting Pancreatic Beta-Cell Functions and Survival in Models of Type 2 Diabetes (T2DM).
- Hyperglycemia and hyperlipidemia are phenomena that have been proposed to play a role in T2DM. The current concept is that once the primary pathogenesis of diabetes is established, which is affected by both genetic and environmental factors, hyperglycemia ensues. High circulating glucose and lipid levels in turn exert additional damaging and toxic effects on the β-cells. Using a microarray analysis, we identified inflammatory genes that are significantly upregulated in human islets chronically exposed to high glucose levels and which are under study in the context of T2DM.
 - Glucocorticoids-Induced Diabetes. Glucocorticoid hormones (GCs) are widely used to treat a variety of inflammatory and immune diseases. However, their long-term administration is associated with adverse metabolic effects, including glucose intolerance and diabetes. Our objective is to elucidate the mechanisms by which GCs affect β-cell survival with a specific emphasis on the role of the thioredoxin-interacting protein (Txnip) in β-cell apoptosis.
The Transcription Factor Pancreatic Duodenal Homeobox-1 (PDX-1) Plays a Key Role in Pancreatic Development and in Beta-Cell Function.  Our laboratory has originally identified the role of pancreatic duodenal homeobox-1 (PDX-1) in regulating glucose-mediated insulin transcription in adult β-cells. We are investigating how this crucial factor is affected under hyperglycemic, hyperlipidemic conditions and in glucocorticoid-induced diabetes.
- Role of the Transcription Factor NF-kB in Regulating Pancreatic Beta-Cell Survival in Models of Type 1 Diabetes (T1DM).  Increasing evidence indicate that β-cell apoptosis is a pathological feature that seems to be common to both Type 1 diabetes (T1DM) and following islet transplantation. In T1DM β-cells are selectively destroyed following the infiltration of inflammatory cells into the islets. One mechanism postulates that these inflammatory cells release cytokines that are toxic for β-cells. Specific transcription factors play key roles in the control of cell death and survival. In β-cells, the transcription factor NF-B appears to be an important regulator of genes that lead to apoptosis. The primary objectives of our research are directed towards understanding the molecular mechanisms involved in the role of this transcription factor in processes leading to the survival/death of β-cells.  Thus, we generated two transgenic mouse models, the ToIβ and the ToIβ-NOD (mouse model of T1DM) lines where the NF-kB pathway can specifically be turned off/on in pancreatic β-cells in an inducible manner. Our aims are to evaluate the effect of NF-kB blockade on diabetes development and on islet grafts survival in different transplantation models.
Elucidating the molecular mechanisms and signaling pathways leading to initiation of β-cell dysfunction and death is crucial for the development of strategies that preserve adequate β-cell mass and insulin production. 
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