INVESTIGATIONS OF AMYLOIDOGENESIS

近年来，蛋白质沉积疾病已得到更好的理解。 年这些疾病的斑块类型被称为 淀粉样蛋白在许多器官中形成。这被发现是由 由蛋白质组成的微观细丝或“原纤维”， 身体的组成部分。其中最著名的是神经学 老年痴呆症等疾病。最近人们发现， 帕金森病也福尔斯这一类。另一类 神经系统疾病是脑病，如克-雅二氏病 在人类中，BSC（或“疯牛病”）在牛和羊瘙痒症。虽然 这些在人类中是非常罕见的，他们是相当关注，因为它已经 研究表明，参与其中的蛋白质，所谓的“朊病毒”， 把疾病从牛传染给人。其中一个最大的谜团是 疾病的关键在于了解正常的蛋白质成分是如何 身体开始改变形成这些斑块。 在拟议的研究中，Doniach博士和他的同事将调查 淀粉样纤维形成的分子基础， 已知参与沉积疾病的蛋白质：AL淀粉样变性， α-突触核蛋白（帕金森氏症）和两个模型系统。除了生化 测量，他们将执行时间分辨小角度X射线散射 淀粉样蛋白形成蛋白及其突变体的溶液的测量， 为了研究自缔合的动力学以及 低聚物在其形成的途径上形成。长期目标是 研究将是获得足够的信息，分子脱轨， 纤维的形成，这样最终就有可能设计药物， 减缓或可能抑制沉积过程， 是这类疾病的根源

Protein deposition diseases have become better understood in recent years. These are diseases where plaque of a type which is termed 'amyloid' forms in a number of organs. This is found to be composed of microscopic filaments or 'fibrils' made out of proteins which are normal constituents of the body. The most well known of these are neurological diseases such as Alzheimer's disease. More recently it has been discovered that Parkinson's disease also falls into this category. Another class of neurological diseases is the encephalopathies such as Creuzfeld-Jacob disease in humans, BSC (or 'mad cow disease') in cattle and scrapie in sheep. Although these are very rare in humans, they are of considerable concern since it has been shown that the proteins involved, so-called 'prions' appear to actually transmit the disease from cows to humans. One of the big mysteries in this kind of disease is understanding how perfectly normal protein constituents of the body start to change in a way that forms these plaques. In the proposed research Dr. Doniach and his colleagues will investigate the molecular basis for formation of amyloid fibrils by studying a number of proteins which are known to be involved in deposition diseases: AL amyloidosis, alpha-synuclein (Parkinson's) and two model systems. In addition to biochemical measurements, they will perform time-resolved small angle x-ray scattering measurements on solutions of the amyloid forming proteins and their mutants in order to study the kinetics of self-association and the size and shape of oligomers formed on the pathway to their formation. The long term aim of this research will be to gain sufficient information about the molecular derails of fibril formation so that eventually it will be possible to design drugs for slowing down or possibly inhibiting the deposition process which is believed to be at the root of this class of disease.