Activation and in vivo Functions of Initiator Caspases

描述（由申请人提供）：内在凋亡途径涉及线粒体的破坏和线粒体蛋白的释放，导致半胱天冬酶-9和下游半胱天冬酶级联的激活。虽然细胞死亡仍然可以继续在caspase-9的情况下，它被推迟在caspase-9缺陷B细胞与自噬的显着诱导。提出实验来验证这样的假设：caspase-9和自噬之间的相互作用在调节程序性细胞死亡中发挥着重要作用。自噬可能通过清除受损的线粒体来帮助防止细胞死亡：1）研究在线粒体膜电位部分丧失后拯救caspase-9缺陷的B细胞的机制; 2）确定自噬促进B细胞存活的机制; 3）研究caspase-9和自噬在体内调节淋巴细胞发育和功能中的作用。半胱天冬酶信号传导和线粒体自噬在调节程序性细胞死亡中的相互作用将被研究。这项研究将有助于深入了解细胞死亡过程中线粒体自噬调控的分子机制。通过自噬调控线粒体质量在预防衰老、癌症和神经退行性疾病中发挥重要作用。这项研究可能有助于开发更好的策略来治疗涉及异常线粒体自噬的疾病。公共卫生相关性：该项目旨在研究半胱天冬酶和自噬对程序性细胞死亡的调节。

DESCRIPTION (provided by applicant): The intrinsic apoptosis pathway involves the disruption of mitochondria and the releases of mitochondrial proteins, leading to the activation of caspase-9 and a downstream caspase cascade. Although cell death can still proceed in the absence of caspase-9, it was delayed in casapse-9-deficient B cells with significant induction of autophagy. Experiments are proposed to test the hypothesis that the interplay between caspase-9 and autophagy plays an important role in regulating programmed cell death. Autophagy may help to protect against cell death by clearing damaged mitochondria: 1) To study the mechanisms for the rescue of caspase-9-deficient B cells after partial loss of mitochondrial membrane potential; 2) To determine the mechanisms by which autophagy promotes the survival of B cells; and 3) To investigate the roles of caspase-9 and autophagy in the regulation of development and functions of lymphocytes in vivo. The interplays between caspase signaling and mitochondrial autophagy in regulating programmed cell death will be investigated. The proposed study will help to gain insights into the molecular mechanisms for the regulation of mitochondrial autophagy during cell death. Mitochondrial quality control by autophagy has been suggested to play essential roles in the prevention against aging, cancer and neurodegenerative diseases. The proposed study may facilitate the development of better strategies for treating diseases involving abnormal mitochondrial autophagy. PUBLIC HEALTH RELEVANCE: This project seeks to investigate the regulation of programmed cell death by caspases and autophagy.