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In vivo mechanisms of amyloid-induced pancreatic islet dysfunction in type 2 diabetes

淀粉样蛋白诱导的 2 型糖尿病胰岛功能障碍的体内机制

基本信息

批准号：
10588374
负责人：
Jordan James Wright
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588374
关键词：
Affect Alpha Cell Alzheimer&apos s Disease Amputation Amyloid Apoptosis Area Behavior Beta Cell Binding Bioinformatics Biology Blindness Blood Vessels Cell Death Cell Membrane Permeability Cell Survival Cells Cellular biology Communication Data Science Deposition Development Development Plans Developmental Biology Diabetes Mellitus Disease Education Etiology Foundations Functional disorder Gene Expression Gene Expression Profile Genetic Transcription Glucagon Health Human Hyperglycemia Imaging Techniques Immunoglobulins Immunology In Vitro Individual Inflammation Inflammatory Insulin Insulin Resistance International Islet Cell Islets of Langerhans Kidney Failure Knockout Mice Knowledge Laboratories Ligands Measurement Measures Mediating Mentors Mentorship Methodology Methods Modeling Molecular Monitor Mus Myocardial Infarction National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear RNA Oxidative Stress Pathogenesis Pattern recognition receptor Physiology Process Reagent Receptor Activation Reporting Research Research Design Risk Rodent Rodent Model Role Signal Pathway Signal Transduction Structure Structure of alpha Cell of islet Techniques Technology Testing Time Toxic effect Training Transgenic Mice Transplantation Veterans Viral Visualization Work amylin receptor amyloid formation anterior chamber career development cell type collaborative environment cost diabetes pathogenesis endoplasmic reticulum stress experimental study extracellular eye chamber genetic manipulation human tissue improved in vivo innovation insulin secretion intravital imaging islet islet amyloid polypeptide knock-down longitudinal analysis member mouse model multidisciplinary novel novel strategies prevent programs protein aggregation receptor receptor binding receptor for advanced glycation endproducts receptor-mediated signaling response skills small hairpin RNA transcriptome sequencing transcriptomic profiling

项目摘要

PROJECT SUMMARY / ABSTRACT Type 2 diabetes (T2D) affects 20% of veterans and costs the VA almost $1.5 billion annually. In addition to insulin resistance, the hyperglycemia that defines T2D is caused by insufficient insulin secretion and dysregulated glucagon secretion from the β and α cells of pancreatic islets. T2D islets are also characterized by changes in vasculature, increased inflammation, and deposition of insoluble amyloid, composed primarily of islet amyloid polypeptide (IAPP). Soluble IAPP oligomers, rather than the amyloid itself, are toxic to β cells, through various postulated mechanisms including ER stress, oxidative stress, membrane permeabilization, and receptor-mediated signaling. The receptor for advanced glycation endproducts (RAGE), which binds several extracellular ligands and activates intracellular inflammatory signaling pathways, was recently shown to bind IAPP oligomers and mediate IAPP oligomer-induced toxicity in β cells using cell and islet culture models and transgenic mouse models. However, it is unknown if IAPP-RAGE signaling occurs in human islets, if such signaling occurs in non-β islet cells including α cells, what effect IAPP-RAGE signaling in specific cell types has on human islet function, and what specific RAGE signaling pathways are activated in human islet cells. I hypothesize that IAPP oligomer-induced activation of RAGE receptors on β and ⍺ cells modulates human islet function and health in vitro and in vivo. To test my hypothesis and fill these knowledge gaps, I will leverage four new experimental techniques to study primary human islet cells: 1) recently developed pseudoislet methodology that allows efficient cell-specific genetic manipulation of human islets; 2) transplantation of human pseudoislets into mice to enable longitudinal analysis of structure and function in vivo; 3) modified intravital imaging techniques to visualize amyloid formation and cell death longitudinally; 4) single nuclear isolation and sequencing technologies to detect changes in gene expression in transduced pseudoislets. In Aim 1, I will test the hypothesis that RAGE mediates IAPP oligomer-induced β cell dysfunction in human islets in vitro and in vivo. In Aim 2, I will test the hypothesis that IAPP-RAGE signaling in ⍺ cells causes dysregulated glucagon secretion in human islets in vitro and in vivo. These experiments will clarify fundamental processes in T2D pathogenesis and help identify novel targets to treat and prevent T2D. I will complete these aims as part of an intensive supervised career development plan with oversight and guidance from an expert multi-disciplinary mentoring committee. I will receive formal and informal training in five fundamental areas: 1) new and emerging experimental techniques; 2) scientific education; 3) presentation and communication skills; 4) professional development; and 5) laboratory management. These skills and the results of my proposed experiments will form a strong foundation for my independent research program as I work to improve the understanding and treatment of diabetes mellitus. Project Summary-Page 1

项目摘要/摘要