Mechanisms of Prion Misfolding

朊病毒错误折叠的机制

基本信息

批准号：
7778691
负责人：
PEDRO FERNANDEZ-FUNEZ
金额：
$ 5.95万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778691
关键词：
ATPase Domain Ablation Acceleration Accounting Address Affect Age Alleles Alzheimer&apos s Disease Amyloid fibers Animals Anti-Ulcer Agents Antibodies Area Behavioral Binding Binding Proteins Biochemical Biochemistry Biogenesis Biological Assay Biological Models Biology Boxing Brain Brain Diseases Brain imaging Breeding Buffers Cell Culture Techniques Cell Death Cell Size Cell Survival Cell model Cell physiology Cells Cellular Morphology Cellular Stress Cellular biology Cessation of life Characteristics Chemicals Cleaved cell Clinical Co-Immunoprecipitations Complementary DNA Complex Confocal Microscopy Control Animal Coupled Creutzfeldt-Jakob Syndrome Cultured Cells Cytolysis Cytoplasm Cytoplasmic Granules DNA DNA Sequence Data Degradation Pathway Deposition Detergents Deterioration Development Digestion Dimethyl Sulfoxide Disease Disease Progression Disease model Dominant-Negative Mutation Dot Immunoblotting Drosophila genus Drosophila melanogaster Electrons Embryo Endopeptidase K Endoplasmic Reticulum Ensure Epitopes Event Exhibits Face Fatal Familial Insomnia Female Figs - dietary Foundations Freezing Functional RNA Future Geldanamycin Generations Genes Genetic Genetic Polymorphism Genetic Transcription Genets Genotype Glycoproteins Goals Guanidines Hamsters Hand Head Health Heat-Shock Response Heating Hematoxylin and Eosin Staining Method Hippocampus (Brain)Histology Homeostasis Hour Human Immunity Immunoblotting Immunoprecipitation In Situ Nick-End Labeling In Vitro Incubated Individual Infection Infectious Agent Inherited Intraperitoneal Injections Invertebrates Knock-out Knockout Mice Kuru Laboratories LacZ Genes Lead Learning Left Left cerebral hemisphere Light Link Literature Lobe Mammalian Cell Mammals Measures Mediating Membrane Mesocricetus auratus Messenger RNA Methodology Microscopic Modeling Molecular Molecular Chaperones Molecular Conformation Molecular Genetics Molecular Weight Monitor Morphology Mus Mushroom Bodies Mutant Strains Mice Myopathy Nature Nerve Degeneration Nervous System Physiology Neurobiology Neuroblastoma Neurodegenerative Disorders Neuronal Dysfunction Neurons Nucleic Acid Regulatory Sequences Open Reading Frames Oryctolagus cuniculus Palliative Care Paraffin Embedding Parkinson Disease Partner in relationship Pathogenesis Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phase Phenotype Phosphorus Physiologic pulse Physiological Planet Mars Plant Resins Positioning Attribute Postdoctoral Fellow Powder dose form PrPSc Proteins Preparation Prion Diseases Prions Procedures Process Promega Property Protein Conformation Protein Isoforms Proteins Publishing Pyroxylin Rattus Recombinants Relative (related person)Reporter Reporting Research Research Design Research Personnel Research Project Grants Resistance Resources Reverse Transcriptase Polymerase Chain Reaction Right cerebral hemisphere Risk Risk Factors Rodent Role Safety Sagittaria Sampling Scrapie Sepharose Shapes Signal Transduction Small Interfering RNA Sodium Solubility Sonication Spinocerebellar Ataxias Staining method Stains Structure Study models Surface Symptoms Syndrome System Tauopathies Techniques Technology Testing Therapeutic Therapeutic Intervention Thick Thinking Time Toxic effect Transcript Transfection Transgenes Transgenic Animals Transgenic Mice Transgenic Organisms Transmission Electron Microscopy Tubulin Type 1 Spinocerebellar Ataxia U6 small nuclear RNA Urea Validation Variant Western Blotting Wild Type Mouse Work abstracting aged analytical tool arimoclomol axonal degeneration base benzonase combinatorial conformational conversion conformer cresyl violet design dopaminergic neuron dosage endoplasmic reticulum stress experience feeding fibrillogenesis flexibility fly gain of function geranylgeranylacetone guanidine thiocyanate human disease immunoreactivity in vivo infected vector rodent innovation insight interdisciplinary approach interest killings male medical schools mouse model multicatalytic endopeptidase complex mutant nervous system disorder neurodegenerative phenotype neuron loss neuronal cell body neuropathology neuroprotection neurotoxic neurotoxicity novel novel strategies overexpression polyglutamine prevent prion hypothesis programs promoter protective effect protein aggregate protein aggregation protein complex protein expression protein misfolding protein misfolding cyclic amplification protein phosphatase inhibitor-2 research study response sarkosyl spinal and bulbar muscular atrophy success synergism synuclein tissue preparation tool trafficking transcription factor vector

项目摘要

ABSTRACT- area 07 Prion diseases are a group of aggressive, lethal and incurable neurodegenerative disorders. The hallmark pathological event in these maladies is the misfolding, aggregation and brain deposition of ?scrapie? Prion protein (PrPSc), which leads to spongiform degeneration of brain neurons. Unfortunately, a major gap exists in our understanding of how the conformational conversion of PrP ultimately kills neurons. Recent in vitro studies suggest that molecular chaperones may be key factors mediating PrP conversion and neuronal dysfunction. However, the functional relevance of this finding is unknown. My central hypothesis is that targeted expression of molecular chaperones can suppress PrP misfolding and PrP-mediated neurodegeneration. To that end, I created a novel and powerful Drosophila model of sporadic prion disease in which wild type PrP from Hamster converts into PrPSc?like conformations and causes spongiform degeneration. Supporting my hypothesis, human Hsp70 prevents PrP misfolding and protects against PrP-dependent neurotoxicity in transgenic flies. The overall goal of this project is to define the role of molecular chaperones in PrP misfolding by a multidisciplinary approach that combines the power of Drosophila genetics with mammalian cellular systems and mice. My specific aims are: 1) Genetic, biochemical and pharmacological approaches to study Hsp70 protection against PrP misfolding and neurotoxicity in Drosophila; 2) Determination of the ability of the Unfolded Protein Response components XBP1s and Grp58 to suppress PrP misfolding and neurotoxicity in Drosophila; 3) Role of molecular chaperones in prion replication in simplified mammalian systems, and 4) Potential therapeutic role of Hsp70 in mouse models of prion diseases. I anticipate that our studies will contribute to better understand the molecular basis underlying PrP conversion. In addition, by exploring the role of chaperone-inducing compounds in flies and mice, I may discover effective and innovative therapeutic interventions for treating these devastating and yet incurable diseases.

摘要- 07区朊病毒病是一组侵袭性、致命性和无法治愈的神经退行性疾病。标志这些疾病的病理事件是“痒病”的错误折叠、聚集和脑沉积。朊病毒蛋白质（PrPSc），导致大脑神经元海绵状变性。不幸的是，存在重大差距我们对 PrP 构象转变如何最终杀死神经元的理解。最近的体外研究表明分子伴侣可能是介导 PrP 转化和神经元功能障碍的关键因素。然而，这一发现的功能相关性尚不清楚。我的中心假设是有针对性的分子伴侣的表达可以抑制 PrP 错误折叠和 PrP 介导的神经变性。到为此，我创建了一种新颖且强大的散发性朊病毒病果蝇模型，其中野生型 PrP 来自仓鼠的转化为 PrPSc? 样构象并导致海绵状变性。支持我的假设，人类 Hsp70 可以防止 PrP 错误折叠并防止 PrP 依赖性神经毒性转基因果蝇。该项目的总体目标是确定分子伴侣在 PrP 错误折叠中的作用通过将果蝇遗传学与哺乳动物细胞的力量相结合的多学科方法系统和鼠标。我的具体目标是：1）遗传、生化和药理学方法的研究 Hsp70 对果蝇 PrP 错误折叠和神经毒性的保护作用； 2) 能力的确定未折叠的蛋白质反应成分 XBP1s 和 Grp58 可抑制 PrP 错误折叠和神经毒性果蝇； 3) 分子伴侣在简化哺乳动物系统中朊病毒复制中的作用，以及 4) Hsp70 在朊病毒疾病小鼠模型中的潜在治疗作用。我预计我们的研究将有助于更好地理解 PrP 转化的分子基础。此外，通过探索伴侣诱导化合物在果蝇和小鼠中的作用，我可能会发现有效和创新的治疗方法治疗这些毁灭性且无法治愈的疾病的干预措施。