CROSSTALK BETWEEN NGF RECEPTORS, TRK A AND P75

NGF 受体、TRK A 和 P75 之间的串扰

• 批准号: 6285871
• 负责人: SUNG OK YOON
• 金额: $ 32.51万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6285871
• 关键词: JUN kinase; apoptosis; biological signal transduction; cell growth regulation; genetically modified animals; growth factor receptors; laboratory mouse; nerve growth factors; oligodendroglia; phosphatidylinositol 3 kinase

DESCRIPTION (From the Applicant's Abstract): The overall goal of this project is to understand the signaling mechanisms underlying cell death and survival, using NGF as a model. As a member of the neurotrophin family, NGF regulates the balance between cell survival and death in the nervous system both during development and in adulthood. An imbalance in this regulation can cause a variety of neurodegenerative diseases such as Alzheimer's and Parkinson's. NGF exerts its effects by binding to the cell surface via two distinct types of receptors, TrkA and p75, each capable of eliciting its own signaling response. NGF can either promote neuronal survival or death and this dichotomous action depends on the outcome of the interplay between TrkA and P75. Specifically when JNK, a kinase, is activated by p75, cell die and when suppressed by TrkA, cells live. The primary objective of this application is to investigate the mechanism of TrkA/p75 crosstalk in oligodendrocytes. Our overall hypothesis is that TrkA/p75 crosstalk takes the form of direct, competitive regulation at a particular point in the pathway upstream of JNK. To test this hypothesis, the following specific aims are proposed: Aim 1 to test whether p75 signaling is required for apoptosis. We will investigate whether oligodendrocytes die in the absence of p75, and whether we can reconstitute the missing effect by introducing back into the p75-/- oligodendrocytes the full-length p75 of the mutant p75 lacking the signaling domain. Aim 11: to test whether Rac functions as the upstream regulator in the JNK pathway and whether TrkA and p75 regulate Rac activity oppositely. Aim 111: to investigate the mechanisms whereby Trk-A mediated PI-3kinase activity suppresses JNK activation. The outcome of this study will result in significant advancement of the current knowledge of NGF signaling by elucidating the basic biochemical mechanisms behind the complex interplay between TrkA and p75. In addition, delineation of the process controlling the precise balance between cell death and survival by NGF may lead to the development of potential therapeutic agents for many degenerative diseases whose etiology may reflect a dis-regulation in this balance.

描述(摘自申请者摘要)：本项目的总体目标 是为了了解细胞死亡和存活背后的信号机制， 使用NGF作为模型。作为神经营养因子家族的一员，NGF调节 神经系统中细胞存活和死亡之间的平衡 发展阶段和成年阶段。这一规定的不平衡可能会导致 多种神经退行性疾病，如阿尔茨海默氏症和帕金森氏症。 通过两种不同类型的结合到细胞表面来发挥其作用 受体，TrkA和p75，每个都能引起自己的信号反应。 NGF既可以促进神经元存活，也可以促进神经元死亡，这种二分性作用 取决于TrkA和P75之间相互作用的结果。特别是在什么情况下 JNK是一种激酶，被p75激活，细胞死亡，当被TrkA抑制时，细胞 活着。这个应用程序的主要目标是研究其机制 TrkA/p75串扰在少突胶质细胞中的表达。我们的总体假设是 TrkA/P75串扰以直接、竞争性的方式 JNK上游小路上的一个特殊地点。为了检验这一假设， 提出了以下具体目标：目标1测试p75信号是否 是细胞凋亡所必需的。我们将调查少突胶质细胞是否在 P75的缺失，以及我们是否可以通过 将p75-/-少突胶质细胞的全长p75重新引入p75-/-少突胶质细胞 缺失信号域的突变体p75。目标11：测试RAC是否正常工作 作为JNK途径的上游调节因子，TrkA和p75是否调节 RAC活动正好相反。目标111：研究Trk-A的作用机制 介导的PI-3K活性抑制JNK的激活。这样做的结果是 这项研究将大大提高目前对NGF的认识 通过阐明复合体背后的基本生化机制来传递信号 TrkA和p75之间的相互作用。此外，对过程的描述 通过NGF控制细胞死亡和存活之间的精确平衡可能会导致 对多种退行性疾病的潜在治疗药物的开发 其病因可能反映出这种平衡失调的疾病。