Mechanisms of Neurotrophin dependent Survival

描述（由申请人提供）：在卒中模型中，神经退行性 疾病和发育性细胞死亡，特定神经营养因子的递送 可以保护神经元免于凋亡。因此，了解分子 神经营养因子用于促进细胞存活和保护 神经元损伤可能有助于新的发展 用于神经元病症和与细胞死亡相关的疾病的疗法。 最近的研究已经确定磷脂酰肌醇（PI）3-激酶 Akt蛋白激酶是重要的细胞存活途径 由神经生长因子（NGF）和其他神经营养因子激活。但据 现在越来越清楚的是，神经营养因子利用额外的生存途径。的 本申请的总体目标是测试NGF转导的假设 生存信号通过涉及转录调节因子的途径 核因子κ B（NF-κ B）。将探讨的一个主要主题是， NF-kB通过上调抗凋亡蛋白而促进NGF促进的存活 神经元中的机制。具体目标1将研究 PI 3-激酶/Akt和NF-κ B在神经元中的存活途径。实验将 测试抑制PT 3-激酶/Akt通路是否影响NGF诱导的NF-κ B 激活神经元。其他实验将检查激活是否 都可以保护神经元免于细胞死亡， 其他.具体目标2中的实验将确定细胞死亡事件 在NGF撤除后诱导，可通过激活NF-kB、聚焦 对活性氧、Bax和细胞色素c的影响。具体目标3 目的是鉴定神经元中NF-κ B的促生存转录靶点， 测试这些蛋白质是否作为神经生长因子依赖的生存的一部分， 通路最后一个具体目标（4）中的实验将测试以下内容的重要性： NF-iB的内源性c-Rel亚单位用于神经元存活 C-Re！“淘汰”小鼠。这些实验将共同检验 NF-kB对神经营养因子调节的存活的影响，他们将揭示重要的新 神经营养因子保护神经元的机制 细胞死亡。

DESCRIPTION (provided by applicant): In models of stroke, neurodegenerative disease, and developmental cell death, the delivery of specific neurotrophins can protect neurons from apoptosis. Thus an understanding of the molecular mechanisms that neurotrophins use to promote cell survival and to protect neurons from injury is likely to contribute to the development of novel therapies for neuronal disorders and diseases associated with cell death. Recent studies have firmly established that phosphatidylinositol (PI) 3-kinase and the Akt protein kinase comprise an important cell survival pathway activated by nerve growth factor (NGF) and other neurotrophins. However, it is now becoming clear that neurotrophins utilize additional survival pathways. The overall aim of this application is to test the hypothesis that NGF transduces survival signals through a pathway involving the transcriptional regulator nuclear factor kappa-B (NF-KB). A major theme that will be explored is that NF-kB contributes to NGF-promoted survival by up-regulating anti-apoptotic mechanisms in neurons. Specific aim 1 will investigate the relationship between the PI 3-kinase/Akt and NF-KB survival pathways in neurons. Experiments will test whether inhibiting the PT 3-kinase/Akt pathway effects NGF-induced NF-KB activation in neurons. Additional experiments will examine whether activation of either pathway can protect neurons from cell death caused by inhibiting the other. Experiments in specific aim 2 will determine the cell death events induced after NGF withdrawal that can be blocked by activating NF-kB, focusing on reactive oxygen species, Bax, and cytochrome c. The goal of specific aim 3 is to identify pro-survival transcriptional targets of NF-kB in neurons and to test whether these proteins function as part of a NGF-dependent survival pathway. Experiments in the last specific aim (4) will test the importance of the endogenous c-Rel subunit of NF-iB for neuronal survival using neurons from c-Re! "knockout" mice. Together these experiments will test the importance of NF-kB for neurotrophinregulated survival and they will uncover important new information concerning the mechanisms by which neurotrophins protect neurons from cell death.