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Using ex vivo, in vivo models and patient mutations to interrogate pancreatic exocrine-endocrine cross talk

使用离体、体内模型和患者突变来探究胰腺外分泌-内分泌串扰

基本信息

批准号：
10594228
负责人：
Saumya Das
金额：
$ 95.84万
依托单位：
JOSLIN DIABETES 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：
2022-09-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594228
关键词：
2&apos -Deoxythymidine Acinar Cell Address Anatomy Autophagocytosis Beta Cell Biological Models Biology Cardiovascular Diseases Cause of Death Cell Communication Cell Line Cell physiology Cell secretion Cells Cellular Stress Cellular biology Coculture Techniques Communication Communities Complement Data Data Set Defect Development Diabetes Mellitus Disease Disease Progression Duct (organ) structure Ductal Epithelial Cell Embryonic Development Endocrine Esters Exhibits Exocrine pancreas Extracellular Space Functional disorder Gene Mutation Genes Genetically Engineered Mouse Goals Growth Hip region structure Hormones Human Incubated Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Kidney Failure Label Lipase Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Modeling Molecular Morbidity - disease rate Mutation Organoids Outcome Pancreas Pancreatic Diseases Pancreatitis Pathogenesis Pathway interactions Patients Physiology Process Property Reagent Research Resolution Resources Role Secondary to Slice Small RNA Testing Therapeutic Tissues Transfer RNA Transplantation Variant blood glucose regulation cell type combat diabetes risk endoplasmic reticulum stress exosome experimental study extracellular vesicles gene product human disease humanized mouse in vitro Model in vivo in vivo Model induced pluripotent stem cell insight intercellular communication islet lipid disorder mutant non-diabetic novel paracrine risk variant senescence stress granule uptake

项目摘要

PROJECT SUMMARY Type 1 diabetes and its metabolic consequences continue to be among the most significant biomedical challenges in the US and worldwide today. In addition to morbidities specifically related to diabetes the disease is associated with complications such as renal failure, lipid disorders, cardiovascular disease and cancer and is a major cause of death worldwide. Thus there is an urgent need for a better understanding of the pathogenesis that promotes the loss of insulin-secreting beta cells to plan better therapeutics to combat the disease. Several studies have argued that diverse cell types that make up the pancreatic niche contribute to the pathogenesis of the disease process. Thus a better understanding of the inter-cellular communication between major cells such as the acinar and duct cells and islet cells are warranted. We have studied the role of the mutant carboxy ester lipase (CEL) gene, expressed in acinar cells, on its ability to be taken up by beta cells and cause defects in its function and growth. The goal of this proposal is to discover the changes that occur when secretome from acinar versus duct cells are incubated with human islet and β-cells. The data from these studies will generate new hypothesis for testing that will allow a deeper interrogation of the cross-talk between human acinar, duct and islet cells. We will address the following Aims in this proposal: Aim 1) Determine the ability of human acinar versus human duct cells to directly impact islet cell function. We will isolate and characterize EVs, from human induced pluripotent stem (hIPS) cell derived acinar- versus duct-lineage committed organoids, and incubate them with human islet/β-cells and human pancreas slices to directly examine the consequences on islet cell biology. We will also examine the EV cargo with a particular focus on fragments derived from transfer RNAs. Aim 2) We will interrogate the ability of EVs, derived from acinar-derived organoids generated from the hiPS cells from MODY8 patients, to directly regulate human islet-β-cell biology. The use of human organoids and human pancreas slices will provide translational relevance of our studies. The results and datasets obtained from these experiments will complement the efforts of the Human Islet Research Network and provide novel resources to be shared with the larger scientific community.

项目总结