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: 7525050
• 负责人: JIYAN MA
• 金额: $ 32.81万
• 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/7525050
• 关键词: Alzheimer' s Disease; Animals; Binding; Biochemical; Biological; Biological Assay; Brain; C-terminal; Cell Membrane Permeability; Cells; Characteristics; Chimeric Proteins; Condition; Disease; Endopeptidase K; Endopeptidases; 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; Localized; Membrane; Membrane Lipids; Membrane Microdomains; Molecular Conformation; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Numbers; Parkinson Disease; Pathogenesis; Pattern; Peptide Hydrolases; Phosphatidylinositols; Physiological; Pliability; Point Mutation; Poly(A)+ RNA; PrPSc Proteins; Preventive; Prion Diseases; Prions; Process; Protein Binding; Protein Conformation; Proteins; Public Health; Reaction; Recombinants; Resistance; Role; System; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transmembrane Domain; Wild Type Mouse; base; in vitro Assay; insight; middle lung lobe; mutant; novel; prion hypothesis; prophylactic; protein misfolding cyclic amplification; research study; retinal rods; tool; trafficking

DESCRIPTION (provided by applicant): 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 1-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. PUBLIC HEALTH RELEVANCE: 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 diseases.

描述（由申请人提供）：朊病毒病的特征是神经变性、朊病毒蛋白（PrP）构象变化和朊病毒感染性。尽管传染原的物理性质仍存在争议，但令人信服的证据支持朊病毒假说，该假说假设从富含 1 螺旋的 PrPC 到富含 ¿ 片层且耐蛋白酶的 PrPSc 构象的转变是朊病毒感染性的核心。最近的研究表明，其他生理因素在促进 PrP 转化和朊病毒感染性产生方面发挥着关键作用。作为一种 GPI 锚定蛋白，PrP 不断暴露在膜脂环境中，并且 PrP-脂质相互作用已被证明。 PrP 与阴离子脂质结合导致 PrP 构象变化和脂质膜通透性改变。在让人想起生理条件的环境下，阴离子脂质-PrP 相互作用将全长重组 PrP 的很大一部分转化为具有增加的 ¿-片层含量和 PrPSc 样蛋白酶 K 抗性模式的构象。此外，疾病相关突变的影响以及脂质诱导的 PrP 转化和 PrPSc 传播的许多共同特征表明了 PrP-脂质相互作用的生物学相关性。我们提出以下研究来阐明脂膜对朊病毒病发病机制的贡献。在目标 1 中，将使用我们建立的体外测定来剖析 PrP 和脂质之间的相互作用，从而确定 PrP-脂质相互作用的病理生理学意义。此外，还将分析疾病相关的 PrP 突变对 PrP-脂质相互作用的影响。在目标 2 中，将利用生化和动物研究来确定脂质、脂质诱导的 PrP 构象和朊病毒的自我永存特征之间的关系。在目标 3 中，将使用新型转基因小鼠方法研究非筏局部 PrP 对朊病毒感染引起的致病变化的重要性。我们预计我们提出的研究将为我们提供对朊病毒病发病机制的见解，并为制定合理的治疗和预防策略奠定基础。公共健康相关性：这些研究的结果也可能与其他神经退行性疾病有关，例如阿尔茨海默病和帕金森病，其中蛋白质-脂质膜相互作用已被认为是一种常见的致病过程。朊病毒病是一组传染性神经退行性疾病。我们这项提案的目标是了解朊病毒病的致病变化是如何发生的。这些知识将为开发针对这些毁灭性和不治之症的合理预防和治疗方法奠定基础。