Mechanisms of Neurotrophin dependent Survival

描述(申请人提供)：在卒中模型中，神经退行性变 疾病、发育性细胞死亡、特定神经营养因子的传递 可以保护神经元免受细胞凋亡的影响。因此对分子的理解 神经营养因子促进细胞存活和保护细胞的机制 来自损伤的神经元可能有助于新奇生物的发展 神经元疾病和与细胞死亡相关的疾病的治疗。 最近的研究证实，磷脂酰肌醇(PI)3-激酶 Akt蛋白激酶是一条重要的细胞生存途径 由神经生长因子(NGF)和其他神经营养因子激活。然而，它是 现在越来越清楚的是，神经营养因子利用了额外的生存途径。这个 这个应用程序的总体目标是测试NGF转导的假设 通过涉及转录调节因子的途径发出生存信号 核因子-kappaB(NF-kB)。将探讨的一个主要主题是 核因子-kB通过上调抗细胞凋亡作用促进NGF促存活 神经元中的机制。具体目标1将调查两者之间的关系 PI3-K/Akt和核因子-kB在神经元中的生存途径。实验将会 检测抑制PT3-K/Akt通路对NGF诱导的核因子-KB的影响 神经元的激活。更多的实验将检验激活 任何一种途径都可以保护神经元免受因抑制细胞死亡而导致的细胞死亡 其他的。特定目标2的实验将确定细胞死亡事件 NGF戒断后诱导，可通过激活核因子-kB，聚焦 关于活性氧、Bax和细胞色素c.特定目标3 是确定神经元中核因子-kB的促生存转录靶点，并 测试这些蛋白质是否作为NGF依赖生存的一部分发挥作用 路径。在最后一个特定目标(4)中的实验将检验 神经营养因子-IB的内源性c-Rel亚单位对神经元存活的影响 C-Re！“基因敲除”的老鼠。这些实验将共同检验 核因子-kB用于神经营养调节的生存，他们将发现重要的新 关于神经营养因子保护神经元的机制的信息 死于细胞死亡。

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.