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.

项目概要 1 型糖尿病及其代谢后果仍然是最重要的生物医学问题之一除了与糖尿病特别相关的发病率外，当今美国和全世界面临的挑战。与肾衰竭、血脂紊乱、心血管疾病和癌症等并发症相关是全世界死亡的主要原因，因此迫切需要更好地了解其发病机制。促进分泌胰岛素的β细胞的损失，以制定更好的疗法来对抗这种疾病。研究认为，构成胰腺生态位的不同细胞类型有助于糖尿病的发病机制从而更好地了解主要细胞之间的细胞间通讯。因为腺泡、导管细胞和胰岛细胞是必要的，我们已经研究了突变体羧基酯的作用。脂肪酶（CEL）基因，在腺泡细胞中表达，其被β细胞吸收并导致其缺陷的能力该提案的目标是发现腺泡分泌蛋白组时发生的变化。导管细胞与人类胰岛和β细胞一起孵育这些研究的数据将产生新的数据。测试假设将允许更深入地研究人类腺泡、导管和我们将在本提案中解决以下目标：目标 1) 确定人类腺泡的能力。与人类导管细胞相比，直接影响胰岛细胞功能我们将从人类中分离和表征 EV。诱导多能干（hIPS）细胞衍生的腺泡与导管谱系定型类器官，并孵化将它们与人类胰岛/β细胞和人类胰腺切片一起直接检查对胰岛细胞的影响我们还将检查 EV 货物，特别关注源自转移 RNA 的片段。目标 2) 我们将探讨由 hiPS 产生的腺泡衍生类器官衍生的 EV 的能力来自 MODY8 患者的细胞，直接调节人类胰岛β细胞生物学。人类胰腺切片将提供我们研究的结果和数据集的转化相关性。这些实验将补充人类胰岛研究网络的努力，并提供新颖的与更大的科学界共享资源。