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Physical Biochemistry and Biology of Amyloid Beta-Protein

β-淀粉样蛋白的物理生物化学和生物学

基本信息

批准号：
8850772
负责人：
DAVID B. TEPLOW
金额：
$ 30.62万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850772
关键词：
Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Biochemistry Bioinformatics Biological Biology Cell Line Cereals Circular Dichroism Country Development Disease Drosophila eye Eye Development Fluorescence Foundations Genes Goals Human Hydroxyl Radical In Vitro Lead Life Light-Scattering Spectroscopy Locomotion Longevity Mass Spectrum Analysis Modeling Molecular Conformation Mutagenesis Neurons Neurotoxins Pathologic Peptides Printing Protein Fragment Proteins Proteolysis Research Resolution Scanning Seeds Seminal Solvents Spectrum Analysis Structure Structure-Activity Relationship System Therapeutic Therapeutic Agents Thioflavin T Time Tissue-Specific Gene Expression United States Work aged biophysical analysis crosslink cytotoxic foot in vivo insight ion mobility molecular dynamics multidisciplinary neurotoxic novel prevent protein oligomer research clinical testing senescence structural biology tau Proteins

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating disease of the aged. Two amyloid-forming proteins are associated with AD, the amyloidß-protein (Aß) and tau. Recent evidence supports an hypothesis, the "amyloid cascade hypothesis," that posits that Aß oligomers are the seminal neuropathogenetic agents in AD. The overall goal of this proposal is to understand the structural biology of Aß, and fragments thereof, and to establish formal structure-activity relationships. In the long run, we seek to obtain an atomic-resolution determination of the structure of the proximate neurotoxins formed by Aß, and in doing so, enable the development, for the first time, of disease-modifying AD treatments. A multidisciplinary strategy, employing complementary experimental and computational approaches, will be employed. This strategy has been used very successfully in the past, providing novel insights into the Aß system. Three specific aims are proposed that systematically and logically progress from in vitro biophysical studies of Aß and its oligomeric assemblies (Aim 1), to in vitro and in vivo studies of the biological activity of selected such assemblies (Aim 2), to determination of the effects of selected assemblies on differential gene expression in neurons (Aim 3). Taken together, these studies will provide the theoretical and experimental foundation for subsequent therapeutic compound development and clinical testing in humans. Aim 1. To determine the structural dynamics of Aß and tau assembly. a. To use scanning Tyr mutagenesis to elucidate mechanisms of Aß oligomerization. b. To determine the dynamics of intramolecular turn formation and its effects on Aß assembly. c. To determine the effects of primary structure changes on the conformations and assembly dynamics of biologically relevant and theoretically important Aß peptides. Aim 2. To determine the biological effects of Aß assemblies. a. To determine the cytotoxic effects of Aß assemblies on cultured neuronal cell lines and primary neurons. b. To determine the effects of Aß assemblies on Drosophila eye development, locomotion, and longevity. Aim 3. To identify and validate AD-relevant genes using a bioinformatics approach that considers Aß assembly structure, neuron type, and neuron senescence.

描述（由申请人提供）：阿尔茨海默病（AD）是一种老年人的毁灭性疾病。两种淀粉样蛋白形成蛋白与AD相关，即淀粉样蛋白-蛋白（AAPs）和tau。最近的证据支持一种假说，即“淀粉样蛋白级联假说”，即假定ApoA寡聚体是AD中的种子神经致病剂。该提案的总体目标是了解Aesthetics及其片段的结构生物学，并建立正式的结构-活性关系。从长远来看，我们寻求获得由Aesthetics形成的近端神经毒素的结构的原子分辨率测定，并且在这样做的过程中，首次能够开发疾病修饰AD治疗。一个多学科的战略，采用互补的实验和计算方法，将采用。这种策略在过去已经非常成功地使用过，为April系统提供了新的见解。提出了三个具体的目标，系统和逻辑的进展，从体外生物物理学研究的Aparthritis及其寡聚体组件（目的1），在体外和体内研究的生物活性的选择这样的组件（目的2），以确定选定的组件对差异基因表达的影响在神经元（目的3）。总之，这些研究将为后续的治疗性化合物开发和人体临床试验提供理论和实验基础。目标1。为了确定Ablast和tau组装的结构动力学。a.目的：利用扫描酪氨酸突变技术阐明腺苷酸寡聚化的机制。B.确定分子内转角形成的动力学及其对AAF组装的影响。C.确定一级结构变化对生物学相关和理论上重要的肽的构象和组装动力学的影响。目标2.确定生物学效应。a.确定ARAPINE组装体对培养的神经元细胞系和原代神经元的细胞毒性作用。B.目的：研究果蝇眼发育、运动和寿命对ARAMINE组装体的影响。目标3。使用生物信息学方法识别和验证AD相关基因，该方法考虑了神经元组装结构、神经元类型和神经元衰老。