Structural Biology of Amyloid Disease

淀粉样蛋白疾病的结构生物学

• 批准号: 8665846
• 负责人: DAVID EISENBERG
• 金额: $ 36.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665846
• 关键词: Alzheimer' s Disease; American; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloid fibers; Amyloidosis; Amyotrophic Lateral Sclerosis; Antibodies; Architecture; Binding; Biochemical; Biological; Caliber; Cells; Chemicals; Collaborations; Complex; Computational algorithm; Cryoelectron Microscopy; Crystallins; Diagnosis; Diagnostic tests; Disease; Exhibits; Fiber; Fluorescence; Goals; Grant; Growth; Homo; Human; Huntington Disease; International; Intervention; Knowledge; Laboratories; Learning; Length; Ligand Binding; Ligands; Malignant Neoplasms; Metabolic Diseases; Methods; Molecular; Needles; Nerve Degeneration; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Parkinson Disease; Pathway interactions; Peptides; Prion Diseases; Prions; Property; Proteins; Roentgen Rays; Running; Shapes; Solutions; Speed; Structure; System; Systemic disease; Testing; Therapeutic; Time; Toxic Actions; Toxic effect; Vacuum; Vertebral column; Work; aggregation pathway; amyloid formation; amyloid structure; base; beta pleated sheet; cell killing; design; frontier; inhibitor/antagonist; insight; pharmacophore; primary amyloidosis of light chain type; small molecule; structural biology; tau Proteins

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.

描述(由申请人提供)：由于缺乏关于淀粉样纤维和低聚物的结构、形成途径和毒性模式的信息，在诊断和治疗淀粉样疾病方面的进展受到阻碍。与对癌症、传染病和代谢性疾病日益成功的治疗相反，淀粉样蛋白疾病的治疗几乎是在对病原体的结构和作用的知识真空中进行的。淀粉样变性疾病不仅包括目前困扰着500多万美国人的阿尔茨海默氏症，还包括帕金森氏症、普里恩病、II型糖尿病、老年性全身性淀粉样变性、轻链淀粉样变性等。所有这些情况都与细长的、直径10-20 nm的未分枝的蛋白质纤维有关，但在每种疾病中，相关的纤维由不同的蛋白质形成。在系统性淀粉样变性疾病中，纤维似乎是病因；在 神经退行性淀粉样变性疾病，纤维形成蛋白的小寡聚体是病因。这个项目的总体目标是在分子水平上了解淀粉样纤维和寡聚体如何形成和杀死细胞。这一知识将加快淀粉样蛋白疾病诊断和治疗的设计和测试。在以前的工作中，我们使用比通常用于结构确定的蛋白质晶体小30,000到100,000倍的晶体来确定纤维和低聚物的结构。这就需要开拓微晶学的新方法。在过去的资助期间，我们用这些新方法确定了大约90个淀粉样蛋白片段的淀粉样纤维结构，揭示了疾病相关纤维的原子水平结构。最近这个 该方法发现了两种新的结构，似乎可以解释Pron聚集和淀粉样蛋白小寡聚体。我们将扩大对这些新型结构的研究，包括它们的形成途径和生物毒性。通过研究淀粉样寡聚体与识别不同蛋白质的有毒寡聚体的抗体的复合体的结构，我们将识别有毒淀粉样寡聚体的共同特征。作为设计针对淀粉样病的化学和生化干预措施的开始，我们已经确定了与淀粉样蛋白片段结合的小分子的原子结构。我们还设计了两种抑制淀粉样纤维生长的药物。在新的授权期内，我们将寻求了解淀粉样蛋白的形成和毒性的机制。由于淀粉样蛋白疾病科学研究的复杂性，我们已经建立了一个广泛的合作者网络--当地的、国家的和国际的--我们与他们分享信息和方法。