TRANSMEMBRANE PRION PROTEIN AND DISEASE

描述(申请人摘要)：监狱疾病包括 遗传性和自发性疾病的异质性群体。更改后的 监狱蛋白(PrP)的形式似乎在他们的 发病机制。在这种可传染的监狱疾病中，一种对蛋白酶具有抵抗力 称为PrPSC的形式在大脑中积累，似乎是 疾病的病原体。然而，在一般性监狱障碍中，PrPSC 通常不会被检测到。相反，新的数据表明，一种跨膜形式 PrP(称为ctmPrP)参与触发脑内神经退行性变 遗传性监狱疾病，正常情况下大脑中的保护因素 阻止ctmPrP表达。申请人提议建立一个明确的 框架，使用转基因小鼠和衍生细胞系，研究其作用 CtmPrP及其相互作用的宿主基因。申请者将会 验证ctmPrP参与通路早期阶段的假设 所有监狱疾病的细胞病理学，以及 疾病和神经细胞死亡是监狱的独立特征 精神错乱。申请人将尝试开发新的生化分析方法，用于 一个或多个经典特征所涉及的分子机制 选定的监狱疾病，如潜伏期，以及性质、程度 以及神经退行性变的位置。通过这项工作，一种新的范式 将建立监狱疾病的发病机制和具体的假设 影响ctmPrP的宿主基因的作用将被测试。建议数 研究为未来对宿主因素的操纵奠定了基础 这可能会保护牢房免受监狱疾病的侵扰。

DESCRIPTION (Applicant's abstract): Prison diseases encompass a heterogeneous group of transmissible and spontaneous disorders. Altered forms of the prison protein (PrP) appear to play a central role in their pathogenesis. In this transmissible prison disorders, a protease-resistant form termed PrPSC accumulates in the brain and appears to be a component of the agent of the disease. However, in the generic prison disorders, PrPSC is often not detected. Instead, new data suggests that a transmembrane form of PrP (termed ctmPrP) is involved in triggering neurodegeneration in genetic prison diseases, and that a protective factor in brain normally prevents ctmPrP expression. The applicant proposes to establish a defined framework, using transgenic mice and derived cell lines, to study the role of both ctmPrP and host genes with which it interacts. The applicant will test the hypotheses that ctmPrP is involved at an early step in the pathway of cellular pathology of all prison diseases, and that transmission of disease and neuronal cell death are independent features of prison disorders. The applicant will attempt to develop new biochemical assays for the molecular mechanisms involved in one or more of the classical features of selected prison diseases, such as incubation time, and the nature, extent and location of neurodegeneration. Through this work, a novel paradigm of prison disease pathogenesis will be established and specific hypotheses on the role of host genes that influence ctmPrP will be tested. The proposed studies set the stage for the future manipulation of host factors in ways that may protect cells from prison disease.