Proteopathies of the Aging Central Nervous

衰老中枢神经的蛋白质病

基本信息

批准号：
7404948
负责人：
Lennart Mucke
金额：
$ 9万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-15 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7404948
关键词：
Abbreviations Address Advisory Committees Affect Age Aging Alzheimer&apos s Disease American Amino Acids Amyloid Amyloid beta-Protein Precursor Animal Experimentation Animal Experiments Animal Model Animals Apolipoprotein E Apolipoproteins Appendix Appointment Area Arts Autopsy Award Back Behavior assessment Behavioral Binding Biochemical Biochemistry Biological Biological Assay Blood Blood Vessels Brain-Derived Neurotrophic Factor Calcium Calcium Channel Calcium-Binding Proteins California Cardiovascular Diseases Caring Cell Death Cells Cellular Neurobiology Cellular biology Central Nervous System Diseases Cessation of life Characteristics Cholinergic Agents Cities Clinic Clinical Collaborations Collection Commit Communities Complex Computer Assisted Computer Viruses Computers Condition Connecticut Corpus striatum structure Cultured Cells Cysteine DNA Microarray Chip DNA Microarray format DNA analysis Daily Data Databases Degenerative Disorder Dependence Deposition Development Disease Dissection Distal Disulfides Doctor of Medicine Doctor of Philosophy Educational process of instructing Educational workshop Electronics End Point Endowment Ensure Environment Epigenetic Process Equipment Experimental Models Extravasation Fab Immunoglobulins Faculty Fellowship Figs - dietary Fostering Foundations Free Radicals Frequencies Functional disorder Funding Future Gene Targeting General Hospitals Generations Genetic Genetic Polymorphism Genomics Goals Head Health Healthcare Systems Hearing Heart Heat shock proteins Hippocampus (Brain)Homeostasis Hospitals Human Human Resources Huntington Disease Image Image Analysis Imagery Immune Impaired cognition Impairment In Vitro Inclusion Bodies Individual Information Services Inherited Institute of Medicine (U.S.)Institutes Institution Internal Medicine International Joints Journals Kentucky Knowledge LDL-Receptor Related Protein 1 Label Laboratories Lasers Lead Leadership Learning Lewy Bodies Lewy Body Disease Life Light Link Lipid Binding Lipoprotein Receptor Lipoproteins Lung Massachusetts Measures Mediating Medical Medicine Membrane Memory Memory impairment Mexico Microscope Microscopic Microscopy Mission Modeling Modification Molecular Molecular Chaperones Molecular Conformation Molecular Neurobiology Molecular Profiling Molecular and Cellular Biology Monoclonal Antibodies Mus Mutation N-Methylaspartate Nerve Degeneration Neuraxis Neuroanatomy Neurobiology Neurodegenerative Disorders Neurofibrillary Tangles Neurologic Neurology Neuronal Dysfunction Neurons Neurosciences Neurovirology Numbers Organic Chemistry Oxidative Stress Paris, France Parkinson Disease Participant Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peer Review Peptides Personal Satisfaction Persons Pharmacogenomics Pharmacologic Substance Physical Chemical Technique Physicians Physiology Pilot Projects Plants Play Polymerase Chain Reaction Pongidae Population Positioning Attribute Postdoctoral Fellow Predisposition Prevention Principal Investigator Procedures Process Production Productivity Program Research Project Grants Property Protein Conformation Protein Isoforms Proteins Proteolysis Publications Publishing Qualifying RNA Range Reading Reagent Recruitment Activity Recycling Relative (related person)Reliability of Results Research Research Activity Research Institute Research Peer Review Research Personnel Residencies Resistance Resources Risk Risk Factors Robotics Rodent Role San Francisco Scanning Science Scientist Secure Seminal Senile Plaques Services Site Slice Social Problems Societies Staging Stress Structure Students Sum Surveys Symptoms Synapses System Talents Technology Testing Therapeutic Time Tissues Toxic effect Training Training Programs Transgenic Mice Transgenic Model Transgenic Organisms Trinucleotide Repeats Trustees United States National Academy of Sciences United States National Institutes of Health Universities Vaccination Variant Visit Week Writing X-Ray Crystallography age related aged animal care apolipoprotein E-3 apolipoprotein E-4 basal forebrain base bench to bedside biophysical chemistry calbindin D calbindin-D28K cell type cellular targeting cholinergic cholinergic neuron clinically significant computer program cost cost effectiveness day defense response dentate gyrus disability dissemination research expectation experience extracellular follow-up foot genetic manipulation genetic risk factor human Huntingtin protein human disease in vitro Assay in vivo innovation insight instrument interest link protein medical schools member motor deficit mouse model multidisciplinary mutant nervous system disorder neurodegenerative phenotype neuroimmunology neuropathology neurophysiology neurotoxic novel peptide A polyglutamine prevent professor programs protein aggregate protein aggregation protein folding protein misfolding protein structure repaired research study success symposium synuclein tau Proteins tissue culture tool uptake

项目摘要

We will address the hypothesis that different neurodegenerative diseases are caused by the accumulation of distinct proteins with pathogenic conformations (proteopathies). These disorders are a complex biomedical, behavioral, and social problem as they are increasing in frequency, cause major disability, and remain largely untreatable. If the ways in which different proteins damage nerve cells overlap, treatments may be developed to prevent and reverse more than one of these conditions. We have assembled five interactive projects and four essential cores to study the mechanisms by which proteins associated with Alzheimer's, Parkinson's, or Huntington's disease impair neuronal function and survival. The program is multidisciplinary and relies on state-of- the-art technology, including X-ray crystallography, robotic microscopy, transgenic and gene-targeted mouse models, cellular biology, neuropathology, and behavioral neuroscience. Project 1, "Polyglutamine Conformation and Neurodegeneration," aims to differentiate whether visible aggregates or other conformational states of mutant huntingtin are responsible for Huntington's disease-related neurodegeneration. Project 2, "Protein Structure in Apolipoprotein E4-associated Neurodegeneration," will test whether the Alzheimer's disease-promoting effect of apolipoprotein E4 depends on the conformation and stability of this molecule. Project 3, "Apolipoprotein E in Neurobiology: Cellular Mechanisms," will examine whether apolipoprotein E4 promotes Alzheimer's disease-like pathology through amyloid 13peptide (A_)-dependent pathways or via independent mechanisms. Project 4, "Causes and Consequences of _-Synuclein Aggregation," will assess whether pathogenic interactions between A[3 and _- synuclein could contribute to the development of PD and other Lewy body diseases. Project 5, "Mechanisms of A[3- induced Neuronal Deficits," aims to identify the molecular cascades that link the formation of neurotoxic A[3 assemblies to Alzheimer's disease-related cognitive decline and will test whether these cascades can be modulated by apolipoprotein E isoforms and _x-synuclein. The Cores (A: Administrative; B: Tissue Culture; C: Animal; D: Neuropathology/Imaging) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them.

我们将解决以下假设：不同的神经退行性疾病是由具有致病构象（蛋白质病）的不同蛋白质。这些疾病是一种复杂的生物医学，行为和社会问题随着频率的增加而导致主要残疾，并且在很大程度上保持无法治疗。如果不同蛋白质损害神经细胞重叠的方式，则可以发展为预防和逆转这些条件之一。我们组装了五个互动项目和四个研究与阿尔茨海默氏症，帕金森氏症或蛋白质相关的蛋白质的基本核心亨廷顿氏病损害神经元功能和生存。该计划是多学科的，依赖于 ART技术，包括X射线晶体学，机器人显微镜，转基因和靶向基因的小鼠模型，细胞生物学，神经病理学和行为神经科学。项目1，“聚谷氨酰胺构象和神经变性，“旨在区分突变体的可见骨料或其他构象状态亨廷顿负责亨廷顿疾病相关的神经变性。项目2，“蛋白质结构载脂蛋白E4相关的神经变性，” 载脂蛋白E4取决于该分子的构象和稳定性。项目3，“载脂蛋白E 神经生物学：细胞机制，“将检查载脂蛋白E4是否促进阿尔茨海默氏病样通过淀粉样蛋白13肽（A _）的病理学 - 依赖性途径或通过独立机制。项目4，“原因 _-核蛋白聚集的后果，”将评估[3和_-之间的致病相互作用突触核蛋白可能有助于PD和其他路易体疾病的发展。项目5，“ [3-的机制诱导的神经元缺陷，“旨在确定将神经毒性A形成联系的分子级联反应[3 阿尔茨海默氏病与认知相关的认知能力下降的组装，并将测试这些级联是否可以调节通过载脂蛋白E同工型和_x-核蛋白。核心（A：行政； B：组织培养； C：Animal; D：神经病理学/成像）将为实现计划的目标提供必要的共同服务项目。我们的研究将阐明各种神经退行性疾病，并可以提供所需的知识更好地治疗和防止它们。