Mechanistic Studies and Inhibition of Islet Amyloid

胰岛淀粉样蛋白的机制研究和抑制

• 批准号: G1100079/1
• 负责人: Daniel Raleigh
• 金额: $ 196.22万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1100079%2F1
• 关键词: Mechanistic; Studies; Inhibition; Islet; Amyloid

A number of debilitating human diseases involve the association and aggregation of normally soluble proteins to form insoluble deposits known as amyloid. Amyloid, or the process of its formation is toxic and has been implicated in more than twenty human disorders ranging from neurodegenerative diseases such as Parkinson disease, Huntington?s disease, and Alzheimer?s disease to type-2 diabetes. The research outlined here focuses on a protein known as Islet Amyloid Polypeptide (IAPP, also known as Amylin). IAPP is a hormone which is released from the pancreatic beta-cells together with insulin. IAPP normally acts as a partner with insulin, but forms amyloid deposits in type-2 diabetes. The deposits are localized in the pancreases, are toxic to the insulin producing pancreatic beta-cells, and play a role in the pathology of the disease by killing beta-cells. There is growing evidence that amyloid formation by IAPP is also a critical factor in the failure of islet cell transplants. Type-2 diabetes is reaching epidemic proportions in the UK, but comparatively little is known about amyloid formation by IAPP. A combination of protein chemistry, biochemistry, cell biology and new biophysical approaches will be used to study amyloid formation by IAPP and its consequences. The work involves the application of new techniques for studying the intermediate steps in the process of amyloid formation. A key goal is to define the process in as much detail as possible since a detailed understanding of amyloid formation is critical for drug development. These studies will be complimented by the development of new inhibitors of IAPP amyloid formation and by the demonstration of new strategies for screening libraries of chemical compounds for potential inhibitors. IAPP is an important protein for study in its own right, but it is also an excellent model system for studies of amyloid formation by other proteins, including proteins involved in neurodegenerative disorders. Outreach to undergraduates, pre-university students, and the general public will involve lectures, lab visits (open days), and the hosting of ?lab experiences? for younger students.

许多使人衰弱的人类疾病涉及到正常可溶性蛋白质的结合和聚集，形成称为淀粉样蛋白的不溶性沉积物。淀粉样蛋白，或其形成的过程是有毒的，并且与二十多种人类疾病有关，包括神经退行性疾病，如帕金森病，亨廷顿？阿尔茨海默病和老年痴呆症？S型糖尿病转变为2型糖尿病这里概述的研究重点是一种被称为胰岛淀粉样多肽（IAPP，也被称为Amylin）的蛋白质。IAPP是一种与胰岛素一起从胰腺细胞中释放出来的激素。IAPP通常与胰岛素一起作用，但在2型糖尿病中形成淀粉样蛋白沉积。这些沉积物局限于胰腺，对产生胰岛素的胰腺β细胞有毒，并通过杀死β细胞在疾病的病理中发挥作用。越来越多的证据表明，IAPP的淀粉样蛋白形成也是导致胰岛细胞移植失败的关键因素。2型糖尿病在英国已达到流行病的程度，但IAPP对淀粉样蛋白形成的了解相对较少。将结合蛋白质化学、生物化学、细胞生物学和新的生物物理学方法来研究IAPP对淀粉样蛋白的形成及其后果。这项工作涉及应用新技术来研究淀粉样蛋白形成过程中的中间步骤。一个关键的目标是尽可能详细地定义这一过程，因为对淀粉样蛋白形成的详细了解对药物开发至关重要。这些研究将受到IAPP淀粉样蛋白形成新抑制剂的开发和潜在抑制剂化合物文库筛选新策略的展示的补充。IAPP本身是一种重要的蛋白质，但它也是研究其他蛋白质（包括与神经退行性疾病有关的蛋白质）形成淀粉样蛋白的良好模型系统。面向本科生、大学预科生和公众的推广活动将包括讲座、实验室参观（开放日）和举办？实验室的经历吗?适合年轻的学生。