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

当受伤时，中枢神经系统（CNS：大脑和脊髓）神经元启动一个精心策划的“自杀”程序，称为细胞凋亡。控制这种自杀程序的元素在不同物种中都是保守的，并且在各种各样的人类中枢神经系统疾病中都有观察到。研究使我们对低等动物中枢神经系统发育过程中细胞凋亡的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。

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.