Membrane Interaction and Membrane Mediated Aggregation of Amylin

膜相互作用和膜介导的胰淀素聚集

• 批准号: 7589145
• 负责人: Ayyalusamy Ramamoorthy
• 金额: $ 22.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589145
• 关键词: Address; Adopted; Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid fibers; Beta Cell; Binding; Cell Death; Cell membrane; Cells; Cellular Membrane; Cholesterol; Deposition; Development; Diabetes Mellitus; Disease; Drug Design; Elderly; Employee Strikes; Environment; Etiology; Exhibits; Fiber; Fluorescence; Future; Gangliosides; Glucose; Human; Individual; Insulin; Islets of Langerhans; Kinetics; Lead; Length; Life; Link; Lipids; Literature; Measurement; Measures; Mediating; Medical; Membrane; Micelles; Molecular; Molecular Conformation; NMR Spectroscopy; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Outcome; Pancreas; Parkinson Disease; Patients; Peptides; Phospholipids; Play; Population; Prevalence; Procedures; Process; Production; Property; Proteins; Rattus; Resolution; Risk Factors; Role; Sequence Homology; Solutions; Sorting - Cell Movement; Spectrum Analysis; Structure; System; Techniques; Testing; Tissues; Toxic effect; age related; amyloid formation; base; cell killing; cell type; cytotoxic; cytotoxicity; design; diabetic; diabetic patient; drug development; inhibitor/antagonist; insight; insulin secretion; islet amyloid polypeptide; killings; novel; public health relevance; research study; response; solid state nuclear magnetic resonance

DESCRIPTION (provided by applicant): The impact of Type II diabetes disease is increasing with the expanding percentage of the elderly within our population. Therefore there is an urgent need for medical procedures to cure this disease. Type II diabetes develops due to a combination of decreased insulin secretion and a decrease in the body's response towards insulin. A key factor in the development of Type II diabetes is the loss of insulin producing beta-cells. The membrane interactions, misfolding and aggregation of human Islet Amyloid Polypeptide (hIAPP) is believed to play crucial roles in this process. Previous studies have shown that hIAPP forms small aggregates that kill beta-cells by disrupting the cellular membrane. However, it is not known exactly what causes this process, how hIAPP disrupts the cell's membrane, and, most importantly, how it can be stopped. In this study we propose to use solid-state NMR spectroscopy and other biophysical techniques to address these questions. We will use fluorescence experiments to understand the kinetics of hIAPP aggregation and to determine the conditions for high-resolution studies using solid-state NMR spectroscopy. Solid-state NMR studies will provide insights into the catalytic role of membranes on the formation of misfolded and toxic forms of hIAPP, and the process of membrane-disruption by hIAPP. This information will be essential to understand what makes some individuals susceptible to Type II diabetes and why Type II diabetes strikes late in life. In addition, solving the high-resolution structure of hIAPP in physiologically-relevant membranes using solid-state NMR techniques will answer why some forms of IAPP (such as the human form) are toxic and others (such as the rat form) with very similar sequences are not. These high-resolution structures will guide the development of drugs to stop the loss of insulin production because of beta cell death. Although the proposed study is focused on hIAPP, the outcome will be of importance to other aging-related diseases such as Alzheimer's disease and Parkinson's disease. PUBLIC HEALTH RELEVANCE: Type II diabetes develops due to a combination of decreased insulin secretion and a decrease in the body's response towards insulin. A key factor in the development of Type II diabetes is the loss of insulin producing beta-cells. The proposed studies will give an understanding of the mechanism of how beta-cells are killed by IAPP and may serve to guide the design of drugs to block the toxic effect of IAPP on insulin producing beta-cells.

描述（由申请人提供）：II型糖尿病的影响随着我国人口中老年人比例的增加而增加。因此，迫切需要医疗程序来治愈这种疾病。II型糖尿病的发展是由于胰岛素分泌减少和身体对胰岛素的反应降低的组合。2型糖尿病的一个关键因素是产生胰岛素的β细胞的损失。人胰岛淀粉样多肽（hIAPP）的膜相互作用、错误折叠和聚集被认为在这一过程中起关键作用。先前的研究表明，hIAPP形成小的聚集体，通过破坏细胞膜杀死β细胞。然而，目前尚不清楚是什么导致了这一过程，hIAPP如何破坏细胞膜，以及最重要的是，如何阻止它。在这项研究中，我们建议使用固态NMR光谱和其他生物物理技术来解决这些问题。我们将使用荧光实验来了解hIAPP聚集的动力学，并确定使用固态NMR光谱进行高分辨率研究的条件。固态核磁共振研究将提供深入了解膜的催化作用，形成错误折叠和有毒形式的hIAPP，和膜破坏的过程中的hIAPP。这些信息对于了解是什么使一些人易患II型糖尿病以及为什么II型糖尿病在生命后期发作至关重要。此外，使用固态NMR技术解决生理相关膜中hIAPP的高分辨率结构将回答为什么某些形式的IAPP（如人类形式）是有毒的，而具有非常相似序列的其他形式（如大鼠形式）则不是。这些高分辨率的结构将指导药物的开发，以阻止由于β细胞死亡而导致的胰岛素产生的损失。虽然这项研究的重点是hIAPP，但其结果对其他与衰老相关的疾病如阿尔茨海默病和帕金森病也很重要。公共卫生相关性：II型糖尿病的发展是由于胰岛素分泌减少和身体对胰岛素的反应降低的组合。2型糖尿病的一个关键因素是产生胰岛素的β细胞的损失。拟议的研究将使人们了解β细胞如何被IAPP杀死的机制，并可能有助于指导药物的设计，以阻断IAPP对胰岛素产生β细胞的毒性作用。