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

项目总结 1型糖尿病及其代谢后果仍然是最重要的生物医学研究之一 当今美国和世界面临的挑战。除了与糖尿病有关的疾病外，这种疾病 与肾功能衰竭、血脂紊乱、心血管疾病和癌症等并发症有关，而且 这是全球范围内的主要死因。因此，迫切需要更好地了解其发病机制。 这促进了分泌胰岛素的β细胞的丧失，以计划更好的治疗方法来对抗这种疾病。几个 研究认为，构成胰腺小窝的不同类型的细胞在胰腺癌的发病机制中起重要作用。 疾病的过程。从而更好地了解主要细胞之间的细胞间通信 腺泡细胞、导管细胞和胰岛细胞是必要的。我们已经研究了突变的羧酸酯的作用。 脂酶(CEL)基因在腺泡细胞中的表达对其被β细胞摄取并导致其缺陷的能力的影响 功能和成长。这项建议的目标是发现从腺泡分泌时所发生的变化 而导管细胞则与人胰岛和β细胞孵育。这些研究的数据将产生新的 用于测试的假设，将允许更深入地询问人体腺泡、导管和导管之间的串扰 胰岛细胞。在这项建议中，我们将解决以下目标：目标1)确定人的腺泡能力 直接影响胰岛细胞的功能。我们将从人类中分离和鉴定电动汽车 诱导多能干细胞(HIPS)来源的腺泡和导管谱系承诺的有机体，并孵化 用人胰岛/β细胞和人胰腺切片直接检测对胰岛细胞的影响 生物学。我们还将审查电动汽车货物，特别是来自转移RNA的片段。 目标2)我们将询问EVS的能力，EVS来源于髋关节产生的腺泡衍生的有机体 从MODY8患者的细胞中，直接调控人胰岛-β-细胞生物学。人类有机体的使用和 人类胰腺切片将为我们的研究提供翻译相关性。获得的结果和数据集 这些实验将补充人类岛屿研究网络的努力，并提供新的 与更大的科学界共享的资源。

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.