Signaling Pathways Regulating Neuronal Survival

描述(由申请人提供)：细胞凋亡是一种特定的方式，通过 包括神经元在内的所有类型的细胞都会死亡。虽然这是一个正常的特征 在神经系统发育中，神经元的凋亡性死亡也会发生在 中风和创伤性损伤后的神经退行性疾病 暴露在神经毒素中。在这些情况下，细胞凋亡是不可取的，而且通常 会导致严重的神经缺陷。这些不同的机制 生理和病理生理刺激使信号通路消失。 正常情况下维持神经元存活的因素还远不清楚。该信号 介导细胞存活的信号转导通路及其分子组成 可方便地在培养条件下进行研究。这类研究已经 确定了许多可能在调节 神经元在体外和体内的存活以及可能受到 神经毒性刺激或在神经病理条件下。这样做的目的是 应用是为了研究两种已知的生存调节作用 分子-Akt激酶和核因子-kB(NF-kappaB)转录 因子--在利用培养细胞进行神经细胞凋亡的成熟范例中 大鼠小脑颗粒神经元。这些神经元在培养中的存活可以 至少由四个因素维持-细胞外钾升高(高K+ 或HK)、IGF-1、环状AMP和锂。尽管激活了不同的分子 在细胞表面，我们的假设是 这些不同的生存因素集中在Akt和/或NF-kappaB上。这个 申请的具体目的如下：1.知道Akt是 胰岛素样生长因子-L介导的生存所必需的，以确定它是否也 参与HK、环磷酸腺苷和锂的促存活作用。2.确定 核因子-kappaB介导HK存活的机制 IGF-1、环磷酸腺苷和锂是否也是生存所必需的。 将特别强调转录的作用 辅活化子CBP和核因子-kappaB抑制剂IkappaB-B。3.确定 Akappat与核因子-kappaB活化在抑制血管内皮细胞生长中的关系 细胞凋亡。

DESCRIPTION (provided by the applicant): Apoptosis is a specific mode by which cells of all types including neurons, die. While a normal feature of the developing nervous system, apoptotic death of neurons also occurs in neurodegenerative diseases, following stroke and traumatic injury, and upon exposure to neurotoxins. In these cases, apoptosis is undesirable and often leads to serious neurological deficits. The mechanisms by which these different physiological and pathophysiological stimuli abrogate the signaling pathways that normally maintain neuronal survival are far from clear. The signal transduction pathways mediating cell survival and the molecular components that comprise them can be conveniently studied in culture. Such studies have identified many molecules that are likely to be important in regulating survival of neurons in vitro as well as in vivo and which might be affected by neurotoxic stimuli or in neuropathologic conditions. The goal of this application is to examine the role of two known survival-regulatory molecules-the Akt kinase and the nuclear factor-KB (NF- kappaB) transcription factor-in a well established paradigm of neuronal apoptosis that uses cultures of rat cerebellar granule neurons. Survival of these neurons in culture can be maintained by at least four factors-elevated extracellular potassium (high K+ or HK), IGF- 1, cyclic AMP, and lithium. Although activating distinct molecules at the cell-surface, our hypothesis is that the signaling pathways utilized by these different survival factors converge on Akt and/or NF- kappaB. The specific aims of the application are as follows: 1. Knowing that Akt is necessary for IGF-l- mediated survival, to determine whether it is also involved in survival promotion by HK, cyclic AMP, and lithium. 2. To determine the mechanism by which NF- kappaB mediates survival by HK and to examine whether it is also required for survival by IGF- 1, cyclic AMP, and lithium. Special emphasis will be placed on the roles of the transcriptional coactivator, CBP, and the NF-kappaB inhibitor, IkappaB-B. 3. To determine the relationship between Akappat and NF-kappaB activation in the inhibition of apoptosis.