Structural Biology of Amyloid Disease

描述（由申请人提供）：由于缺乏关于淀粉样蛋白纤维和低聚物的结构、形成途径和毒性模式的信息，淀粉样蛋白疾病的诊断和治疗进展受到阻碍。与癌症、传染病和代谢性疾病的治疗越来越成功相比，淀粉样蛋白疾病的治疗一直是在对病因的结构和作用几乎一无所知的情况下进行的。淀粉样蛋白疾病不仅包括阿尔茨海默氏症，它折磨着今天超过500万的美国人，还包括帕金森氏症、朊病毒疾病、II型糖尿病、老年性系统性淀粉样变性、轻链淀粉样变性等等。所有这些疾病都与直径10-20nm的细长无分枝蛋白纤维有关，但每种疾病的相关纤维是由不同的蛋白质形成的。在全身性淀粉样蛋白疾病中，纤维似乎是病原；在

DESCRIPTION (provided by applicant): Progress in diagnosing and treating amyloid diseases has been hindered by lack of information on the structures, pathways of formation, and modes of toxicity of amyloid fibers and oligomers. In contrast to the increasingly successful attack on cancer, infectious, and metabolic diseases, treating amyloid diseases has proceeded in a near vacuum of knowledge about the structure and action of the etiologic agents. Amyloid diseases include not only Alzheimer's, which afflicts more than 5 million Americans today, but also Parkinson's, prion diseases, diabetes type II, senile systemic amyloidosis, light chain amyloidosis, and many more. All of these conditions are associated with elongated, unbranched protein fibers, 10-20nm in diameter, but in each disease the associated fiber is formed from a different protein. In the systemic amyloid diseases, fibers seem to be the etiologic agents; in the neurodegenerative amyloid diseases, small oligomers of the fiber-forming proteins are the causative agents. The overall goal of this project is to understand at the molecular level how amyloid fibers and oligomers form and kill cells. This knowledge will speed the design and testing of diagnostics and therapeutics for amyloid diseases. In previous work we determined structures of fibers and oligomers working with crystals that are 30,000 to 100,000 times smaller than the protein crystals normally used for structure determination. This has necessitated pioneering new methods of microcrystallography. With these new methods in the past grant period, we determined structures of some 90 amyloid fiber-like structures of segments of amyloid proteins that reveal the atomic level architecture of disease related fibers. Recently this approach has turned up two new types of structures that seem to explain prion aggregation and amyloid small oligomers. We will extend studies of these new types of structures, including of their pathways of formation and their biological toxicity. And by studying the structure of an amyloid oligomer in complex with an antibody that recognizes toxic oligomers of different proteins, we will identify the common features of toxic amyloid oligomers. As a start to designing chemical and biochemical interventions for amyloid disease, we have determined atomic structures for small molecules bound to amyloid segments. We have also designed two inhibitors of amyloid fiber growth. In the new grant period we will seek to understand the mechanisms of amyloid formation and toxicity. Because of the complexity of the scientific study of amyloid disease, we have developed a wide network of collaborators-local, national, and international--with whom we share information and methods.