Membrane Interaction and Membrane Mediated Aggregation of Amylin

描述(由申请人提供)：随着老年人口比例的增加，II型糖尿病的影响正在增加。因此，迫切需要医疗程序来治愈这种疾病。II型糖尿病是由于胰岛素分泌减少和身体对胰岛素的反应减少所致。II型糖尿病发展的一个关键因素是产生胰岛素的β细胞的丧失。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着关键作用。先前的研究表明，hIAPP形成小聚集体，通过破坏细胞膜杀死β细胞。然而，目前还不清楚到底是什么导致了这一过程，hIAPP是如何破坏细胞膜的，最重要的是，如何阻止它。在这项研究中，我们建议使用固态核磁共振波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，并确定使用固态核磁共振光谱进行高分辨率研究的条件。固态核磁共振研究将有助于深入了解膜在错误折叠和有毒形式的hIAPP的形成中的催化作用，以及hIAPP破坏膜的过程。这些信息对于了解是什么使一些人容易患II型糖尿病以及为什么II型糖尿病在人的晚年发病至关重要。此外，使用固态核磁共振技术解决生理相关膜中hIAPP的高分辨率结构将解释为什么某些形式的IAPP(如人类形式)是有毒的，而另一些具有非常相似序列的IAPP(如大鼠形式)则不是。这些高分辨率结构将指导药物的开发，以阻止因β细胞死亡而导致的胰岛素产生损失。尽管这项拟议的研究侧重于hIAPP，但其结果将对其他与衰老相关的疾病，如阿尔茨海默病和帕金森病具有重要意义。公共卫生相关性：II型糖尿病是由于胰岛素分泌减少和身体对胰岛素的反应减少所致。II型糖尿病发展的一个关键因素是产生胰岛素的β细胞的丧失。拟议中的研究将使人们了解IAPP如何杀死β细胞的机制，并可能指导药物的设计，以阻断IAPP对产生胰岛素的β细胞的毒性作用。

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.