INVESTIGATIONS OF AMYLOIDOGENESIS

近年来，人们对蛋白质沉积疾病有了更好的了解 好几年了。这些疾病的斑块类型被称为 “淀粉样蛋白”存在于许多器官中。这被发现是由以下组成的 由正常蛋白质制成的微细纤维或‘原纤维’ 身体的组成部分。其中最广为人知的是神经病学。 阿尔茨海默氏症等疾病。最近，人们发现 帕金森氏症也属于这一类。另一类 神经系统疾病是指克雅氏病等脑部疾病 在人类中，牛的BSC(或“疯牛病”)和羊的瘙痒病。虽然 这些在人类中非常罕见，它们引起了相当大的关注，因为它 已经证明了所涉及的蛋白质，即所谓的普里恩，似乎实际上 将疾病从牛传染给人。这类事件中最大的谜团之一 疾病的关键是了解细胞内完全正常的蛋白质成分 身体开始发生变化，形成这些斑块。 在拟议的研究中，多尼奇博士和他的同事们将研究 淀粉样蛋白纤维形成的分子基础研究 已知与沉积疾病有关的蛋白质：淀粉样变性， α-突触核蛋白(帕金森氏症)和两个模型系统。除了生化之外 测量，它们将执行时间分辨小角x射线散射 淀粉样蛋白形成蛋白及其突变体溶液的测定 为了研究自缔合的动力学和分子的大小和形状 低聚物在形成它们的途径上形成。这样做的长期目标是 研究将获得关于分子脱轨的足够信息 纤维的形成，这样最终就有可能设计出治疗 减缓或可能抑制沉积过程，据信 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.