ION CHANNEL MODULATION BY THE PRION PROTEIN: A NOVEL TOXIC MECHANISM

朊病毒蛋白对离子通道的调节：一种新的毒性机制

基本信息

批准号：
8282857
负责人：
DAVID A HARRIS
金额：
$ 35.09万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282857
关键词：
Agonist Amino Acids Aminoglycoside Antibiotics Animal Model Animals Applications Grants Attention Biochemical Biological Biological Assay Birth Bleomycin Blood Brain Calcium Cell Culture Techniques Cell Death Cell surface Cells Cessation of life Chemicals Clinical Creutzfeldt-Jakob Syndrome Cultured Cells Data Deletion Mutation Dependence Development Disease Dose Drug Hypersensitivity Exhibits Food Safety Gerstmann-Straussler-Scheinker Disease Glutamate Receptor Glutamates Human Infectious Agent Inherited Ion Channel Kinetics Laboratories Learning Link Longevity Measures Mediating Mediator of activation protein Membrane Glycoproteins Molecular Mus Mutation Nature Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Neurotransmitters Normal Cell Nucleic Acids Organ Pathogenesis Pathology Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Phenotype Physiological Play Point Mutation Positioning Attribute PrPC function PrPSc Proteins Prion Diseases Prions Process Proliferating Property Protein Isoforms Protein Region Proteins Public Health Recombinants Resistance Role Scrapie Signal Pathway Signal Transduction Surveys Techniques Testing Therapeutic Therapeutic Intervention Time Toxic effect Transducers Transgenic Mice Voltage-Clamp Technics base cell type cytotoxicity experimental analysis gain of function mutation human disease in vitro Assay in vitro activity inhibitor/antagonist insight interest killings mouse model mutant neoplastic neurodegenerative phenotype neuropathology neurotoxic neurotoxicity novel public health relevance research study response tool voltage

项目摘要

DESCRIPTION (provided by applicant): A great deal is now known about the chemical nature of prions and the mechanism by which they propagate. In contrast, how abnormal forms of the prion protein (PrP) kill nerve cells is still a mystery. There is evidence that the neurotoxicity of prions lies in their ability to alter or subvert a normal, physiological function of PrPC, the cellular form of PrP, but the details of this process are obscure. Tg(?CR) mice, which express a mutant PrP deleted for residues 105-125, provide powerful insights into prion related pathogenic mechanisms. These animals spontaneously develop a severe neurodegenerative illness that is reversed in a dose-dependent fashion by co-expression of wild-type PrP. We have been interested in elucidating the cellular and molecular mechanisms underlying the powerful toxicity of PrP?CR. We have recently discovered that the ?CR deletion acts as a dominant, gain-of-function mutation that strongly activates an ion channel activity that is intrinsic to, or is indirectly induced by, PrP. Moreover, we have found that disease-associated point mutations in the central region of PrP have a similar effect, suggesting that some familial prion diseases are due to excitotoxic activation of ion channels. In this application, we propose to critically test an "ion channel hypothesis" of prion diseases. First, we will survey all known human mutations in the central region of PrP for their effect on ion channel activity in vitro. We will then undertake characterization of the biophysical properties of the channels induced by PrP molecules carrying point and deletion mutations in the central region. Finally, we will determine if excitotoxic activation of ionotropic glutamate receptors plays a role in the neuronal death and neuropathology induced by mutant PrP molecules and infectious PrPSc. The pathogenic mechanisms elucidated in this project are likely to have wide applicability, since abnormal activation of ion channels is a well established paradigm in a number of other neurodegenerative diseases and animal models. Moreover, identification of specific ion channel targets for PrP-mediated toxicity would represent the first step in development of an entirely new class of anti-prion drugs that inhibit cellular neurotoxic pathways, rather than PrPSc propagation. PUBLIC HEALTH RELEVANCE: Prion diseases are fatal neurodegenerative disorders of humans and animals that pose a grave threat to public health, and endanger the safety of the food, blood and organ supplies. This application will explore a novel mechanism of prion pathogenesis based on abnormalities in the ion channels that control electrical activity in the nervous system. This project represents the first step in development of an entirely new class of anti-prion drugs that inhibit cellular neurotoxic pathways, rather than prion propagation.

描述（由申请人提供）：现在人们对朊病毒的化学性质及其繁殖机制有了很多了解。相比之下，异常形式的朊病毒蛋白（PrP）如何杀死神经细胞仍然是一个谜。有证据表明，朊病毒的神经毒性在于它们能够改变或破坏 PrPC（PrP 的细胞形式）的正常生理功能，但这一过程的细节尚不清楚。 Tg(?CR) 小鼠表达残基 105-125 缺失的突变型 PrP，为朊病毒相关致病机制提供了有力的见解。这些动物自发地患上严重的神经退行性疾病，这种疾病可以通过野生型 PrP 的共表达以剂量依赖性方式逆转。我们一直对阐明 PrP?CR 强大毒性的细胞和分子机制感兴趣。我们最近发现，?CR 缺失作为显性的功能获得性突变，强烈激活 PrP 固有的或由 PrP 间接诱导的离子通道活性。此外，我们发现PrP中心区域的疾病相关点突变也有类似的作用，这表明一些家族性朊病毒疾病是由于离子通道的兴奋性毒性激活所致。在此应用中，我们建议严格测试朊病毒疾病的“离子通道假说”。首先，我们将调查 PrP 中心区域所有已知的人类突变对体外离子通道活性的影响。然后，我们将对中心区域携带点突变和缺失突变的 PrP 分子诱导的通道的生物物理特性进行表征。最后，我们将确定离子型谷氨酸受体的兴奋毒性激活是否在突变型 PrP 分子和感染性 PrPSc 诱导的神经元死亡和神经病理学中发挥作用。该项目阐明的致病机制可能具有广泛的适用性，因为离子通道的异常激活是许多其他神经退行性疾病和动物模型中公认的范例。此外，确定 PrP 介导的毒性的特定离子通道靶点将代表开发一类全新的抗朊病毒药物的第一步，该药物可抑制细胞神经毒性途径，而不是 PrPSc 传播。公共卫生相关性：朊病毒病是人类和动物致命的神经退行性疾病，对公众健康构成严重威胁，并危及食品、血液和器官供应的安全。该应用将探索一种基于控制神经系统电活动的离子通道异常的朊病毒发病机制。该项目代表了开发一类全新的抗朊病毒药物的第一步，该药物抑制细胞神经毒性途径，而不是抑制朊病毒的传播。