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: 7657390
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657390
• 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; public health relevance; 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(申请人提供)：Prion病的特征是神经退行性变、PrP构象变化和Prion感染性。尽管感染性病原体的物理性质仍有争议，但有令人信服的证据支持普里恩假说，该假说认为从富含1螺旋的PrPC到富含1螺旋和抗蛋白酶的PrPSc构象的转换是普恩感染性的核心。最近的研究表明，其他生理因素(S)在促进PrP转化和PrP感染性的产生中起着关键作用。PrP作为一种GPI锚定蛋白，经常暴露在膜脂环境中，并且PrP与脂类之间存在相互作用。PrP与阴离子脂类结合导致PrP构象变化和脂膜通透性改变。在令人联想到生理条件的环境中，阴离子脂-PrP相互作用将很大一部分全长重组PrP转化为具有更多折叠含量的构象和PrPSc样蛋白酶K抗性模式。此外，PrP-脂质相互作用的生物学相关性被疾病相关突变的影响以及脂质诱导的PrP转换和PrPSc繁殖所共有的许多特征所表明。我们建议进行以下研究，以阐明脂膜在Pron病发病机制中的作用。在目标1中，PrP-脂质相互作用的病理生理学意义将用我们建立的体外实验来确定，以剖析PrP和脂质之间的相互作用。此外，还将分析与疾病相关的PrP突变对PrP-脂质相互作用的影响。在目标2中，将通过生物化学和动物研究来确定脂质、脂质诱导的PrP构象和PrP的自持性之间的关系。在目标3中，将使用一种新的转基因小鼠方法来研究非RAFT定位的PrP在PrP感染引起的致病变化中的重要性。我们期望我们提出的研究将为我们提供对Pron病发病机制的洞察力，并形成合理的治疗和预防策略的基础。公共卫生相关性：这些研究的结果也可能与其他神经退行性疾病相关，如阿尔茨海默病和帕金森氏病，在这些疾病中，蛋白质-脂膜相互作用被认为是一种常见的致病过程。Pron病是一组感染性神经退行性疾病。我们这项建议的目的是要了解Pron病的致病变化是如何发生的。这些知识将构成针对这些毁灭性和不治之症制定基本的预防和治疗方法的基础。