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

细胞凋亡过程中调节 PI3 激酶和 MAP 激酶途径的分子相互作用

• 批准号: 355802-2012
• 负责人: Koeberle, Paulo
• 金额: $ 1.89万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572662
• 关键词: Molecular; Interactions; modulate; PI3; Kinase

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.

当受伤时，中枢神经系统（CNS：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件在不同物种中是保守的，并且在各种各样的人类CNS疾病中观察到。研究已经导致对低等动物CNS发育过程中细胞凋亡机制的更完整的理解。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。 我的目标是发展的触发器和机制的理解，在成年哺乳动物中枢神经系统的细胞凋亡，使用视神经横断模型的视觉系统。视神经切断导致90%的视网膜神经节细胞（RGC）在14天内凋亡性死亡。该模型系统也是有利的，因为在正常非允许的CNS内，也可以在视神经挤压后检查RGC轴突再生。 我们正在研究两种防止神经元凋亡的途径的调节：磷酸肌醇-3激酶（PI 3 K）和丝裂原活化蛋白激酶（MAPK）途径。我们已经确定了几种蛋白质（PTEN，Erbin，Bcr），拮抗这些途径的活性，并开发了肽拮抗剂，以阻止这种内源性抑制活性。在未来，我们将使用这些抑制肽来揭示PTEN，Erbin和Bcr如何调节细胞死亡。我们最近还确定了RIP家族（受体相互作用蛋白）中蛋白质的促凋亡作用。我们的长期研究将使用我们独特的成年神经元凋亡的哺乳动物模型来表征RIPs如何适应凋亡等级。 我们的研究将弥合哺乳动物物种和低等动物之间的知识差距，细胞凋亡已被更清楚地定义。这是理解人类中枢神经系统许多疾病的重要进展，其中细胞凋亡是神经元变性的主要机制。