CROSSTALK BETWEEN NGF RECEPTORS, TRK A AND P75

描述（来自申请人摘要）：本项目的总体目标 是了解细胞死亡和存活的信号机制， 使用神经生长因子作为模型。作为神经营养因子家族的一员，神经生长因子调节神经细胞的生长， 无论是在过程中还是在过程中，神经系统中细胞存活和死亡之间的平衡 发展和成年。这种调节的不平衡可能导致 各种神经退行性疾病，如阿尔茨海默氏症和帕金森氏症。NGF 通过两种不同类型的蛋白质与细胞表面结合来发挥其作用。 受体，TrkA和p75，每一个都能够引发自己的信号反应。 神经生长因子可以促进神经元存活或死亡， 这取决于TrkA和P75之间相互作用的结果。特别是当 JNK是一种激酶，被p75激活，细胞死亡，当被TrkA抑制时，细胞死亡。 live.本申请的主要目的是研究 少突胶质细胞中TrkA/p75串扰的研究。我们的总体假设是 TrkA/p75串扰以直接竞争性调节的形式存在， JNK上游通路中的特定点。为了验证这一假设， 提出了以下具体目标：目标1，测试p75信号传导是否是 凋亡所必需的。我们将研究少突胶质细胞是否在 p75的缺失，以及我们是否可以通过以下方法重建缺失的效应： 向p75-/-少突胶质细胞中引入p75-/-寡突胶质细胞的全长p75， 缺乏信号传导结构域的突变型p75。目标11：测试Rac是否起作用 作为JNK通路的上游调节因子，以及TrkA和p75是否调节 Rac活性相反。目的111：研究Trk-A 介导的PI-3激酶活性抑制JNK活化。这场 这项研究将导致对神经生长因子的现有知识的重大进展 通过阐明复合物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，该过程的描述 通过NGF控制细胞死亡和存活之间的精确平衡可能导致 涉及许多退行性疾病的潜在治疗剂的开发 病因学可能反映这种平衡失调的疾病。

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.