Presenilin Biology and the Mechanism of Alzheimer's Disease

早老素生物学和阿尔茨海默病的机制

基本信息

批准号：
8318127
负责人：
DENNIS J SELKOE
金额：
$ 122.1万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318127
关键词：
Address Affinity Chromatography Alzheimer&apos s Disease Amyloid Animal Model Animals Applied Research Basic Science Binding Binding Proteins Biochemical Biological Biological Assay Biology Brain Brain region CD44 gene Candidate Disease Gene Cell Line Cell physiology Cell surface Cell-Cell Adhesion Cells Cellular biology Cerebrum Cessation of life Chemistry Cholesterol Cleaved cell Clinical Cognition Collaborations Complex Coupled Cryoelectron Microscopy Crystallography Cut protein Data Dementia Disease E-Cadherin Employee Strikes Endosomes Enzymes ErbB4 gene Etiology Event Exhibits Family Fluorescence Funding Gangliosides Genes Genetic Goals Grant Group Meetings Growth Factor Health Heart Image Individual Institute of Medicine (U.S.)Ions Joints Journals Laboratories Lead Leadership Length Life Light Linkage Disequilibrium Lipids Measures Membrane Membrane Lipids Memory Metabolic Pathway Microscopic Microscopy Missense Mutation Molecular Biology Molecular Conformation Monitor Mutation NGFR gene National Institute of Mental Health Neuronal Dysfunction Neurons Notch Signaling Pathway Output Paper Pathogenesis Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Phospholipids Polymers Postdoctoral Fellow Preparation Presenile Alzheimer Dementia Process Production Program Research Project Grants Progress Reports Protein Binding Protein Conformation Proteins Proteomics Protocols documentation Publications Publishing Reading Reagent Receptor Protein-Tyrosine Kinases Regulation Reporting Research Research Personnel Research Project Grants Resolution Role Running Sampling Scientist Series Signal Transduction Sodium Channel Specificity Structure Structure-Activity Relationship Sum Synapses Syndrome System Techniques Time Transcriptional Regulation United States National Institutes of Health Validation Vision Work association cortex base data exchange design experience functional genomics genome-wide graduate student human APH-1 protein human PEN-2 protein imaging modality interest meetings nectin neurotrophic factor notch protein novel presenilin presenilin-1 programs protein complex research study secretase structural biology trend voltage working group

项目摘要

DESCRIPTION (provided by applicant): The discovery of presenilins as ubiquitous intramembrane proteases in metazoans exemplifies an emerging trend in biology. The traditional distinction between basic and applied research has become increasingly blurred, as studies initiated with a strictly disease-oriented focus uncover fundamental biological mechanisms. In this renewal application, ten investigators who have collaborated successfully during the last decade on the normal and pathological biology of presenilin (PS) wish to extend their productive interactions into new experiments that will further illuminate the structure-function relationships of PS/ ? -secretase in normal biology and the role of this unusual multi-protein complex and various related gene products in the genesis of Alzheimer's disease. Based on extensive preliminary data in each of our four interrelated projects and supported by three vital cores, we will pursue numerous Specific Aims that include: 1. attempting to determine the structure of PS/ ?-secretase by performing cryo-electron microscopy of the purified, active complex as well as x-ray crystallography of the individual components; 2. extending our recent discovery that cholesterol dramatically enhances the catalytic activity of purified ? -secretase and that membrane lipids in general appear to represent the most potent regulators of both A¿ production and Notch cleavage; 3. performing extensive genomic, functional genetic and protein analyses searching for novel lateonset AD candidate genes potentially implicated in presenilin-related pathways; 4. using advanced microscopy approaches in living cells (bimolecular fluorescence complementation; FLIM) to image and quantify the conformations and interactions of presenilin with APP, with new candidate genes emerging from (2), and with lipids and ? -modulating compounds identified herein; 5. identifying common binding partners and common subcellular processing pathways for the (32 subunit of NaJ, APP and APLP2, three proteins that are processed identically by both (3- and y-secretase. 6. performing an unbiased proteomics screen to more fully define the " ? -secretome", i.e., the extent of unknown ?-substrates. These and numerous additional aims and sub-aims will be pursued collaboratively across our 4 projects, with progress in one project modifying experimental plans in another. In short, we are anxious to continue our close interaction to bring greater clarity to exactly how PS and its associated proteins and lipids process a host of substrates within membranes in health and disease. Lay summary: Ten experienced scientists who have collaborated productively for the past decade wish to address the structure and the functions of an unusual protein-cutting enzyme that is required for life in all multi-cellular animals and implicated in the causation of Alzheimer's disease.

描述（通过应用程序提供）：在后生动物中发现presenilins是无处不在的膜内蛋白酶，这是生物学中新兴趋势的发现。基本研究和应用研究之间的传统疾病变得越来越模糊，因为以严格的面向疾病的焦点揭示了基本生物学机制的研究。在此续签应用中，在过去十年中成功合作的十名研究人员就Presenilin（PS）的正常生物学（PS）希望将其生产性相互作用扩展到新实验中，以进一步照亮PS/的结构 - 功能关系？ - 分泌酶在正常生物学中以及这种不寻常的多蛋白质复合物和各种相关基因产物在阿尔茨海默氏病的起源中的作用。基于四个相互关联的项目中的每个项目的广泛初步数据，并在三个重要核心的支持下，我们将追求许多特定的目标，其中包括：1。试图通过执行纯化的，有效的复杂复合物以及单个组件的X射线晶体学的冷冻电子显微镜来确定PS/？ - 分泌酶的结构； 2。扩展了我们最近发现胆固醇会显着增强纯化的催化活性吗？ - 分泌酶和一般外观的膜脂质，代表了生产和缺口裂解的最有效调节剂； 3。进行广泛的基因组，功能性遗传和蛋白质分析，以搜索潜在地在列米蛋白相关途径中实现的新型Lateonset Ad候选基因； 4。使用先进的显微镜方法（双分子荧光完成； FLIM）来形象和量化呈现呈现蛋白与APP的构象和相互作用，并与（2）和脂质以及与脂质以及？ - 调节本文确定的化合物； 5。确定（32个Naj，App和Aplp2的亚基，三种蛋白质，三种蛋白质的常见结合伴侣和常见的亚细胞处理途径，这些蛋白质都与（3-和Y-分泌酶（3-和Y-分泌酶）进行了相同处理。6。执行无偏见的蛋白质组学筛选以更详细地确定“？ - secretome”的范围。在我们的四个项目中进行协作，一个项目在一个项目中进行了改进的计划，我们渴望继续进行近距离互动，以使PS及其相关的蛋白质及其相关的蛋白质和脂质如何处理，并在健康和疾病中进行了效率，并在结构上进行了协作，并将其与之协作。为所有多细胞动物的生命而言，与阿尔茨海默氏病的原因有关。