The role of amino acid status as a signaling event and the pathway by which it signals resulting in ? cell apoptosis has not been evaluated as a causative event. Beyond the consequences of hyperglycemia and hyperlipidemia, additional molecular mechanism (s) that cause ? cell apoptosis during development of diabetes are not well studied but will be vital for the development of novel diagnostic and therapeutic strategies. Apoptosis of ? cells in Type 2 Diabetes (T2DM) is associated with increased stress in the endoplasmic reticulum (ER). Our laboratory has contributed a body of work on the cellular responses to diverse stress conditions, including ER stress and amino acid limitation. Combined work from many labs has shown that the cellular response to ER stress involves the translation and transcriptional reprogramming of cells. We discovered a novel anabolic program that accompanies the translational recovery of late ER stress. This program promotes amino acid uptake, increased tRNA charging, and increased expression of genes involved in protein synthesis. This program which has prosurvival and growth actions under mild stress, paradoxically, promote apoptosis under conditions of chronic stress, by stimulating protein synthesis, by inducing the production of reactive oxygen species, and by exhausting the ATP supply. We propose to study the molecular mechanism of this novel 'suicide' adaptive stress response in insulinoma cells and islets from diabetic mouse models. We will study (i) the mechanisms of transcriptional and translational control, (ii) the mechanism and significance of increased amino acid uptake in the regulation of mRNA translation and (iii) the mechanism via which increased methionine and cystine uptake contribute to protection of ? cells from ER stress-induced apoptosis. Our studies will reveal novel biomarkers in ER stress-induced diabetes (a condition related to T2DM), with diagnostic and therapeutic potential.
Anabolic cellular responses are associated with growth, proliferation and increased metabolic activity. They are usually observed in tumor cells. We made the unexpected finding that insulin-producing pancreatic ? cells induce an anabolic gene expression program in response to stress in the endoplasmic reticulum (ER). ER stress in ? cells is associated with ? cell apoptosis in Type 2 Diabetes (T2DM), an important feature of the disease. In this proposal we will study the components of this anabolic program that lead to apoptosis of ? cells. We aim to discover novel biomarkers for diagnosis and treatment of T2DM.
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