Mechanisms of Islet Amyloidogenesis

胰岛淀粉样蛋白生成的机制

基本信息

批准号：
8117189
负责人：
Steven Emanuel Kahn
金额：
$ 28.26万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117189
关键词：
Address Amino Acid Sequence Amyloid Amyloid Fibrils Amyloid deposition Anabolism Apoptosis Area Cell Death Cell Survival Cell physiology Cells Cellular Stress Clinical Cytokine Activation Deposition Development Disease Environment Functional disorder Future Genetic Risk Goals Health Human Hyperglycemia In Vitro Individual Inflammatory Insulin Insulin Resistance Islet Cell Islets of Langerhans Transplantation Learning MAPK8 gene Measurement Measures Modeling Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Pancreas Pathogenesis Pathway interactions Peptides Production Proteins Research Risk Rodent Rodent Model Role Secretory Cell Signal Pathway Site Stress Time Transgenic Mice Transplantation Weight amyloid formation amyloidogenesis base cell killing cytokine cytotoxic cytotoxicity functional disability glucose tolerance in vivo islet islet amyloid polypeptide mouse model prevent species difference

项目摘要

DESCRIPTION (provided by applicant): Islet amyloid is associated with decreased ¿-cell mass and decreased ¿-cell function in type 2 diabetes. The unique peptide component of these amyloid deposits is islet amyloid polypeptide (IAPP). We hypothesize that in the presence of ¿-cell dysfunction, increased ¿-cell secretory demand results in the deposition of IAPP as islet amyloid. Under these conditions, the accumulation of this amyloidogenic peptide occurs by increased production and is associated with activation of stress-activated cellular signaling pathways leading to ¿-cell apoptosis. Three major specific aims focusing on the pathogenesis and impact of islet amyloid will address this hypothesis. 1. To determine the site of islet amyloid formation and how this determines its cytotoxicity; 2. To determine the role of oxidative stress and inflammatory stress in islet amyloid formation in vitro; and 3. To determine whether oxidative stress and proinflammatory cytokines are determinants of amyloid deposition in vivo. We will measure islet, ¿-cell and amyloid areas, rates of ¿-cell replication and apoptosis, islet cell viability, islet content of insulin and IAPP, ¿-cell secretory function, markers of oxidative stress, proinflammatory cytokines, and activation of the NF-?B and JNK pathways. Measurements will be made in two different models of islet amyloidogenesis (in vitro islet culture and in vivo islet transplantation), both based on our human IAPP transgenic mouse model of islet amyloid. These studies will provide important information about the pathogenesis of islet amyloid and should thus allow the future development of approaches to prevent ¿-cell loss and the development and progression of type 2 diabetes. PUBLIC HEALTH RELEVANCE: Protein deposits called amyloid accumulate in the pancreas and destroy insulin producing cells, thus contributing to the development of type 2 diabetes. This proposal will examine mechanisms by which these deposits form in order to try and prevent their formation and the loss of insulin producing cells.

描述（由适用提供）：胰岛淀粉样蛋白与2型糖尿病中的细胞质量减少和改善的细胞功能有关。这些淀粉样蛋白沉积物胰岛多肽（IAPP）的独特肽成分。我们假设在存在 - 细胞功能障碍的情况下，增加了细胞秘书的需求会导致IAPP作为胰岛淀粉样蛋白的沉积。在这些条件下，这种淀粉样蛋白生成肽的积累是通过增加的产生而发生的，并且与应激激活的细胞信号传导途径的激活有关。重点关注胰岛淀粉样蛋白的发病机理和影响的三个主要特定目的将解决这一假设。 1。确定胰岛淀粉样蛋白形成的部位以及如何确定其细胞毒性； 2。确定体外胰岛淀粉样蛋白形成中氧化应激和炎症应激的作用； 3。确定氧化应激和促炎细胞因子是否由体内淀粉样蛋白沉积确定。我们将测量胰岛，细胞和淀粉样区域， - 细胞复制和凋亡的速率，胰岛细胞生存力，胰岛素和IAPP的胰岛含量， - 细胞秘书秘书功能，氧化物胁迫的标志，促炎细胞因子以及NF-？B？b和JNK路径的激活。测量将在两种不同的胰岛淀粉样生成模型（体外胰岛培养和体内胰岛移植）中进行，均基于我们的人类IAPP转基因小鼠胰岛淀粉样蛋白的模型。这些研究将提供有关胰岛淀粉样蛋白的发病机理的重要信息，因此应允许未来开发用于预防细胞损失以及2型糖尿病的发展和进展的方法。公共卫生相关性：称为淀粉样蛋白的蛋白质沉积物积聚在胰腺中并破坏产生胰岛素的细胞，从而有助于2型糖尿病的发展。该建议将检查这些沉积物形成的机制，以试图防止其形成和胰岛素产生细胞的丧失。