Molecular Interactions that modulate PI3 Kinase and MAP Kinase pathways during apoptosis

当中枢神经系统(CNS：脑和脊髓)神经元受伤时，神经元会启动精心策划的“自杀”程序，称为细胞凋亡。控制这种自杀计划的元素在不同的物种中都是保守的，并在各种人类中枢神经系统疾病中观察到。研究使人们对低等动物中枢神经系统发育过程中的细胞凋亡机制有了更全面的了解。然而，对成年哺乳动物中枢神经系统神经元的这一过程知之甚少。 我的目标是利用视觉系统中的视神经横断模型，发展对成年哺乳动物中枢神经系统中细胞凋亡的触发和机制的理解。视神经切断可导致90%的视网膜神经节细胞(RGC)在14天内死亡。这个模型系统也是有利的，因为视神经挤压后，也可以检查正常情况下不允许的中枢神经系统内的RGC轴突再生。 我们正在研究两个防止神经元凋亡的通路的调节：磷脂酰肌醇-3激酶(PI3K)和丝裂原活化蛋白激酶(MAPK)通路。我们已经确定了几种蛋白(PTEN、Erbin、BCR)可以拮抗这些通路的活性，并开发了多肽拮抗剂来阻断这种内源性抑制活性。未来，我们将利用这些抑制肽来揭示PTEN、Erbin和BCR是如何调控细胞死亡的。我们最近还确定了RIP家族(受体相互作用蛋白)中的蛋白质具有促凋亡作用。我们的长期研究将使用我们独特的成年神经元凋亡哺乳动物模型来表征RIPs如何适应凋亡层次。 我们的研究将弥合哺乳动物物种和低等动物之间的知识鸿沟，在这些物种中，细胞凋亡已经得到了更明确的定义。这是了解人类中枢神经系统多种疾病的重要进展，在这些疾病中，细胞凋亡是神经元退化的主要机制。

When injured, central nervous system (CNS: brain and spinal cord) neurons initiate a carefully orchestrated "suicide" program, called apoptosis. The elements that control this suicide program are conserved throughout different species and observed in a wide variety of human diseases of the CNS. Research has lead to a more complete understanding of the mechanisms of apoptosis during development of CNS in lower animals. However, relatively little is known about this process in adult mammalian CNS neurons. My objective is to develop an understanding of the triggers and mechanisms of apoptosis in the adult mammalian CNS, using the optic nerve transection model in the visual system. Optic nerve transection results in the apoptotic death of 90% of retinal ganglion cells (RGCs) within 14 days. This model system is also advantageous because RGC axon regeneration, within the normally non-permissive CNS, can also be examined after optic nerve crush. We are studying the regulation of two pathways that prevent neuron apoptosis: the phosphoinositide-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways. We have identified several proteins (PTEN, Erbin, Bcr) that antagonize the activity of these pathways, and developed peptide antagonists to block this endogenous inhibitory activity. In the future, we will use these inhibitory peptides to reveal how PTEN, Erbin and Bcr regulate cell death. We have also recently identified a pro-apoptotic role for proteins in the RIP family (receptor interacting proteins). Our long term studies will characterize how RIPs fit into the apoptotic hierarchy using our unique mammalian models of adult neuron apoptosis. Our studies will bridge the knowledge gap between mammalian species and lower animals where apoptosis has been more clearly defined. This is an important development towards understanding numerous diseases of the CNS in humans, where apoptosis is the primary mechanism of neuron degeneration.