Signaling Pathways Regulating Neuronal Survival

描述（由申请人提供）：细胞凋亡是一种特异性模式， 包括神经元在内的所有类型的细胞死亡。虽然一个正常的功能， 在神经系统发育过程中，神经元的凋亡也发生在 神经退行性疾病，中风和创伤性损伤后， 暴露于神经毒素在这些情况下，细胞凋亡是不希望的，并且通常 会导致严重的神经功能缺损这些不同的机制 生理和病理生理刺激消除了信号通路 正常情况下维持神经元存活的机制还很不清楚。信号 介导细胞存活的转导途径和 包括它们的组合物可以方便地在培养中研究。这类研究 确定了许多可能在调节 神经元的存活在体外以及在体内，并可能受到 神经毒性刺激或神经病理条件下。这个目标 应用程序是检查两个已知的生存调节的作用， 分子-Akt激酶和核因子-KB（NF-κ B）转录 因子-在使用培养物的神经元凋亡的良好建立的范例中 大鼠小脑颗粒神经元。这些神经元在培养物中的存活可以 维持至少四个因素-升高的细胞外钾（高K+ 或HK）、IGF- 1、环AMP和锂。尽管激活了不同的分子 在细胞表面，我们的假设是， 这些不同的存活因子集中在Akt和/或NF-κ B上。的 本申请的具体目的如下：1.知道Akt是 IGF-I介导的存活所必需的，以确定其是否也是 参与HK、环AMP和锂的生存促进。2.以确定 NF-κ B通过HK介导存活的机制， 它是否也是IGF- 1、环AMP和锂的生存所必需的。 特别强调的是转录的作用， 辅激活剂CBP和NF-κ B抑制剂IkappaB-B。3.确定 Akappat和NF-κ B活化在抑制 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.