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Role of RAGE in amyloid-induced pancreatic islet dysfunction in diabetes

RAGE 在淀粉样蛋白诱导的糖尿病胰岛功能障碍中的作用

基本信息

批准号：
10506592
负责人：
Jordan James Wright
金额：
$ 15.99万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2022-09-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10506592
关键词：
Affect Alpha Cell Alzheimer&apos s Disease Amyloid Amyloid deposition Apoptosis Behavior Beta Cell Binding Bioinformatics Biology Blood Vessels Cell Culture Techniques Cell physiology Cells Cellular biology Cessation of life Collaborations Complex Data Science Deposition Developmental Biology Diabetes Mellitus Disease Environment Etiology Functional disorder Gene Expression Gene Expression Profile Genetic Transcription Glucagon Health Human Hyperglycemia Imaging Techniques Immunoglobulins Immunology Impairment In Vitro Individual Inflammation Inflammatory Insulin Insulin Resistance International Islet Cell Islets of Langerhans Knockout Mice Link Measurement Measures Mediating Membrane Mentors Mentorship Methods Modeling Molecular Monitor Mus National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear RNA Organism Oxidative Stress Pathogenesis Pattern recognition receptor Persons Physicians Physiology Preventive Process Reagent Receptor Activation Reporting Research Training Rodent Rodent Model Role Scientist Signal Pathway Signal Transduction Structure Techniques Testing Therapeutic Time Tissues Toxic effect Training Transgenic Mice Transgenic Organisms Transplantation United States Viral amylin receptor amyloid formation anterior chamber cell type collaborative environment endoplasmic reticulum stress eye chamber genetic manipulation human disease human tissue in vivo in vivo Model innovation insulin secretion intravital imaging islet islet amyloid polypeptide knock-down member novel novel strategies pancreatic juice prevent receptor binding receptor for advanced glycation endproducts small hairpin RNA transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY / ABSTRACT In type 2 diabetes (T2D), amyloid deposits composed of islet amyloid polypeptide (IAPP) are found within pancreatic islets. T2D islets also have impaired insulin secretion from β cells, dysregulated glucagon secretion from α cells, increased inflammation, and alterations in vasculature. Among multiple potential mechanisms linking amyloid deposition and islet dysfunction, the receptor for advanced glycation endproducts (RAGE) was recently shown to bind IAPP oligomers and mediate β cell toxicity in vitro, which results were also supported using a transgenic rodent model. But in vitro cell culture models, while valuable, do not fully replicate the complex environmental, intercellular, or temporal changes in living organisms. Furthermore, human and rodent islets differ in function, structure, cellular composition, and gene expression. Thus, to fully understand the pathogenesis of human disease, one must study these processes in human cells and tissues in the in vivo context. Such studies have been limited by the inability to obtain and manipulate these relatively inaccessible human tissues and by the lack of in vivo models in which to study them longitudinally. It therefore remains unknown if endogenously secreted IAPP oligomers act on the RAGE receptor in primary human β cells, if such signaling occurs in α cells, and what effect IAPP-RAGE signaling in specific cell types has on islet function. I hypothesize that IAPP oligomer-induced activation of RAGE receptors on β and α cells impairs human islet function and health in vitro and in vivo. To test my hypothesis using human islets, I will employ four novel techniques and reagents. 1) Our recently reported pseudoislet method will enable efficient genetic manipulation of specific islet cell types prior to reaggregation into functional cell clusters. 2) New intravital imaging techniques will allow longitudinal monitoring of amyloid formation in human pseudoislets transplanted into the mouse anterior chamber of the eye. 3) Transplantation of pseudoislets into a recently developed glucagon knockout mouse will permit accurate measurement of human glucagon secretion in vivo. 4) Application of single nuclear RNA sequencing approaches will permit assessment of transcriptional effects on specific cell types in transplanted 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. Completion of these aims will elucidate key mechanisms responsible for pathogenesis of T2D, opening avenues for study into new preventive and therapeutic approaches. I will benefit from the outstanding environment, collaboration, and mentorship at the Vanderbilt Diabetes Research and Training Center as I transition to independence as a physician-scientist.

项目摘要/摘要