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Molecular Mechanisms Regulating Pancreatic Delta Cell Function and Dysfunction

调节胰腺 Delta 细胞功能和功能障碍的分子机制

基本信息

批准号：
10443333
负责人：
David Aaron Jacobson
金额：
$ 44.96万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443333
关键词：
Ablation Amino Acids Animal Disease Models Calcium-Sensing Receptors Cell physiology Cell secretion Cells Coupled Data Diabetes Mellitus Disease Dominant-Negative Mutation Endoplasmic Reticulum Functional disorder G Protein-Coupled Receptor Signaling G alpha q Protein G-Protein-Coupled Receptors Glucagon Glucose Goals Homeostasis Hormone secretion Human Insulin Islet Cell Islets of Langerhans Knowledge Mediating Medical Membrane Potentials Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Pancreas Pancreatic delta Cell Pathogenesis Pathway interactions Patients Pharmacology Physiological Population Potassium Channel Receptor Signaling Research Research Project Grants Role Signal Transduction Somatostatin Stress Testing Transgenic Mice base blood glucose regulation diabetes pathogenesis diabetic driving force experimental study gain of function mutation insight insulin secretion islet knock-down maturity onset diabetes of the young new therapeutic target receptor response small hairpin RNA

项目摘要

Project Summary Islet glucose-stimulated somatostatin (Sst) secretion is lost in patients with type-2 diabetes (T2D) and in animal models of the disease, which contributes to disrupted glucagon and insulin secretion. It is generally accepted that Sst secretion from -cells occurs in response to elevated intracellular Ca2+, which primarily results from endoplasmic reticulum (ER) Ca2+ (Ca2+ER) release. However, the mechanisms that control -cell Ca2+ER handling and how they are altered in T2D are largely unknown. Data from our lab finds that the islet-enriched two-pore- domain K+ channel, TALK-1, is an ER localized channel in that provides a countercurrent for -cell Ca2+ER release and Ca2+ER leak. TALK-1-mediated augmentation of the electrochemical driving force for -cell Ca2+ER leak con- strains Ca2+ER storage, which limits glucose-stimulated Ca2+ER release and Sst secretion. Further data show that -cell Ca2+ER release and Sst secretion are amplified by glucose-induced allosteric activation of -cell Ca2+-sens- ing receptors (CaSRs). Finally, our preliminary data provide the first evidence that diabetic conditions diminish -cell Ca2+ER storage, which contributes to perturbations in glucose-stimulated Ca2+ handling and Sst secretion under diabetic conditions. Based on these exciting preliminary data, the overall objective of this proposal is to elucidate how -cell Ca2+ER is controlled and becomes disrupted during the pathogenesis of diabetes. This project will test the central hypothesis that glucose-stimulated -cell Sst secretion is amplified by CaSR-mediated Ca2+ER release, which is controlled by TALK-1 channel constraint of Ca2+ER storage. The rationale that underlies this project is that understanding how CaSR and TALK-1 control -cell Ca2+ER handling and Sst secretion will expose novel therapeutic targets for restoring glucose-stimulated Sst secretion and islet hormone secretion in T2D. This project will be accomplished with the following two specific aims: 1) Determine how -cell CaSR controls Ca2+ER handling, Sst secretion, and islet hormone secretion; and 2) Determine how TALK-1 channel control of Ca2+ER release modulates -cell function and dysfunction. Under the first aim, transgenic mice with -cell ablation of CaSR as well as human pseudoislets with ShRNA knockdown of -cell CaSR will be utilized to assess the roles of the Ca2+-sensing receptor during secretagogue modulation of -cell Ca2+ handling and Sst secretion. Aim1 will also determine how depletion of -cell Ca2+ER stores under diabetic conditions impacts CaSR signaling and Sst secretion. Under the second aim, the function TALK-1 channels on -cell Ca2+ER handling and function will be determined in mice with -cell specific ablation of TALK-1 and in human pseudoislets containing either -cells with knockdown of TALK-1 or expressing dominant negative TALK-1 channel subunits. Furthermore, Aim2 will determine how TALK-1 augmentation of -cell Ca2+ER depletion under the stressful conditions associated with diabetes contributes to -cell dysfunction. This project is significant because it is expected to illuminate mecha- nisms that alter -cell Ca2+ER handling and disrupt islet hormone secretion in T2D. Moreover, this project will identify pharmacological strategies for normalizing Sst secretion and reducing islet dysfunction in T2D.

项目总结