To investigate the contributions of lipid membranes to prion disease

研究脂质膜对朊病毒病的贡献

• 批准号: 8282853
• 负责人: JIYAN MA
• 金额: $ 32.16万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282853
• 关键词: Alzheimer' s Disease; Animals; Binding; Biochemical; Biological; Biological Assay; Brain; C-terminal; Cell Membrane Permeability; Cells; Characteristics; Chimeric Proteins; Disease; Endopeptidase K; Environment; Future; GPI Membrane Anchors; Generations; Genetic Polymorphism; Goals; In Vitro; Infection; Infectious Agent; Inherited; Knockout Mice; Knowledge; Lead; Length; Lipid Bilayers; Lipid Binding; Lipids; Liposomes; Membrane; Membrane Lipids; Membrane Microdomains; Molecular Conformation; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pattern; Peptide Hydrolases; Phosphatidylinositols; Physiological; Point Mutation; Poly(A)+ RNA; PrPSc Proteins; Preventive; Prion Diseases; Prions; Process; Protein Binding; Protein Conformation; Proteins; Reaction; Recombinants; Resistance; Role; System; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transmembrane Domain; Wild Type Mouse; base; flexibility; in vitro Assay; insight; mutant; novel; prion hypothesis; prophylactic; protein misfolding cyclic amplification; research study; retinal rods; tool; trafficking

Prion disease is characterized by neurodegeneration, prion protein (PrP) conformational change, and prion infectivity. Although the physical nature of infectious agent is still debated, compelling evidence favors the prion hypothesis, which postulates that the conversion from ¿-helical-rich PrPC to ¿-sheet-rich and protease-resistant PrPSc conformation is central to prion infectivity. Recent studies suggest a key role of other physiological factor(s) in facilitating PrP conversion and generation of prion infectivity. As a GPI-anchored protein, PrP is constantly exposed to the environment of membrane lipids and a PrP-lipid interaction has been demonstrated. The PrP binding to anionic lipids results in PrP conformational change and an alteration in lipid membrane permeability. Under an environment reminiscent of physiological conditions, the anionic lipid-PrP interaction converts a significant portion of full-length recombinant PrP into a conformation with increased ¿-sheet content and a PrPSc-like proteinase K resistant pattern. Moreover, the biological relevance of PrP-lipid interaction is indicated by the influence of disease-associated mutation and the many characteristics shared by lipid-induced PrP conversion and PrPSc propagation. We propose the following studies to elucidate the contributions from lipid membrane to the pathogenesis of prion disease. In Aim 1, the pathophysiological significance of PrP-lipid interaction will be determined using our established in vitro assays to dissect the interaction between PrP and lipid. In addition, the influence of disease-associated PrP mutations on PrP-lipid interaction will be analyzed. In Aim 2, biochemical and animal studies will be used to determine the relationship among lipids, lipid induced PrP conformation and the self-perpetuating characteristic of prion. In Aim 3, the importance of non-raft localized PrP to prion infection-caused pathogenic changes will be studied using a novel transgenic mouse approach. We anticipate that our proposed studies will provide us with insights into the pathogenesis of prion disease and form the basis for developing rational therapeutic and prophylactic strategies. Results from these studies may also be relevant to other neurodegenerative disorders such as Alzheimer and Parkinson's diseases, in which protein-lipid membrane interactions have been proposed as a common pathogenic process. Prion diseases are a group of infectious neurodegenerative diseases. Our goal of this proposal is to understand how the pathogenic changes occur in prion disease. This knowledge will form the basis for developing rationale preventive and therapeutic approaches against these devastating and incurable dieseases.

朊病毒病的特征是神经变性、朊病毒蛋白（PrP）构象变化和朊病毒 传染性虽然感染原的物理性质仍有争议，但令人信服的证据支持朊病毒 假设，该假设假定从富含螺旋的PrPC转化为富含螺旋且具有蛋白酶抗性的PrPC， PrPSc构象是朊病毒感染性的核心。最近的研究表明，其他生理功能的关键作用， 促进PrP转化和朊病毒感染性产生的因素。作为GPI锚定蛋白，PrP是 已经证明了持续暴露于膜脂质环境和PrP-脂质相互作用。 PrP与阴离子脂质的结合导致了PrP构象的变化和脂质膜的改变 磁导率在一种类似生理条件的环境下，阴离子脂质-PrP相互作用 将大部分全长重组PrP转化为具有增加的半折叠含量的构象 和PrPSc样蛋白酶K耐药模式。此外，PrP-脂质相互作用的生物学相关性是 疾病相关突变的影响以及脂质诱导突变所共有的许多特征表明， PrP转化和PrPSc传播。我们建议进行以下研究，以阐明 脂膜蛋白与朊病毒病的发病机制在目的1中，PrP-脂质的病理生理学意义 将使用我们建立的体外测定来确定相互作用，以剖析PrP和 脂质此外，还将分析疾病相关PrP突变对PrP-脂质相互作用的影响。在 目的2、通过生物化学和动物实验研究脂质、脂质诱导的 PrP构象与朊病毒的自我延续特性。在目标3中，非木筏的重要性 将使用一种新的转基因小鼠研究朊病毒感染引起的致病性变化的局部PrP approach.我们期望我们的研究将为我们提供深入了解朊病毒的发病机制 疾病，并形成制定合理的治疗和预防策略的基础。从这些 这些研究也可能与其他神经退行性疾病有关，如阿尔茨海默病和帕金森病。 疾病，其中蛋白质-脂质膜相互作用已被提出为常见的致病过程。朊病毒病是一组传染性神经退行性疾病。我们提出这项建议的目的是 了解朊病毒病的致病变化是如何发生的。这些知识将构成 制定合理的预防和治疗方法来对付这些毁灭性的和无法治愈的疾病。 疾病