Mechanistic Studies and Inhibition of Islet Amyloid

许多使人衰弱的疾病涉及正常可溶性蛋白质的缔合和聚集以形成称为淀粉样蛋白的不溶性沉积物。淀粉样蛋白，或其形成过程是有毒的，并已涉及超过20种人类疾病，从神经退行性疾病，如帕金森病，亨廷顿？老年痴呆症和老年痴呆症？2型糖尿病的发病机制这里概述的研究集中在一种被称为胰岛淀粉样多肽（IAPP，也称为淀粉样蛋白）的蛋白质上。IAPP是一种与胰岛素一起从胰腺β细胞释放的激素。IAPP通常作为胰岛素的伴侣，但在2型糖尿病中形成淀粉样蛋白沉积。沉积物位于胰腺中，对产生胰岛素的胰腺β细胞有毒，并通过杀死β细胞在疾病的病理学中起作用。越来越多的证据表明，IAPP形成淀粉样蛋白也是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，但对IAPP形成淀粉样蛋白知之甚少。蛋白质化学，生物化学，细胞生物学和新的生物物理方法的组合将被用来研究淀粉样蛋白的形成IAPP及其后果。这项工作涉及应用新技术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个过程，因为详细了解淀粉样蛋白的形成对药物开发至关重要。这些研究将得到补充的IAPP淀粉样蛋白形成的新抑制剂的开发和潜在抑制剂的化合物筛选库的新策略的示范。IAPP本身是一种重要的研究蛋白质，但它也是研究其他蛋白质（包括参与神经退行性疾病的蛋白质）形成淀粉样蛋白的极好模型系统。对本科生、预科生和公众的宣传将包括讲座、实验室参观（开放日）和主办？实验室经验？为年轻的学生。

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.