Targets of the Cell Death Proteases

项目概要/摘要 作为动物发育和稳态的一个正常方面，程序性细胞死亡（凋亡）在动物体内起着重要作用。 在维持适当的细胞数量的生理平衡，反对不受控制的重要作用 细胞增殖细胞凋亡的异常失活或激活可导致不受控制的细胞生长或细胞凋亡。 不受控制的细胞死亡，并可能导致人类疾病，如癌症，神经退行性疾病， 自身免疫性疾病本申请的广泛的长期目标是了解分子生物学。 细胞凋亡的控制和执行机制，并利用从研究 细胞凋亡，以促进新方法的发展，在治疗和预防人类疾病引起的 不适当的细胞死亡 细胞凋亡是由进化上保守的细胞死亡途径控制和执行的。这件事的核心 途径是高度特异性的“细胞死亡”蛋白酶家族，即半胱天冬酶，其首先合成为 无活性的蛋白酶前体，随后在细胞凋亡期间通过蛋白水解被激活。细胞活化 死亡蛋白酶触发凋亡细胞的系统和有序的细胞解体， 吞噬细胞几种致敏遗传筛选、基于候选人的反向遗传筛选和生化 已经进行了筛选以鉴定CED-3蛋白酶底物和下游组分， 触发和协调细胞分解和移除事件的途径。这些研究导致了 鉴定20个新的细胞死亡基因和几个候选CED-3底物，其作用于下游或 与CED-3平行，CED-3介导各种细胞死亡执行过程，包括染色体断裂， 线粒体消除，细胞尸体识别/吞噬，以及其他尚未确定的细胞死亡信号传导 和执行事件。本申请的具体目的是：（1）描述候选人的功能 CED-3底物在细胞死亡执行中的作用;（2）鉴定和表征参与CED-3底物在细胞死亡执行中的作用的其他基因。 磷脂酰丝氨酸外化，“吃我”信号，在细胞凋亡过程中;（3）表征基因参与 细胞尸体识别/吞噬及其作用机制;（4）表征影响其他细胞死亡的基因。 细胞死亡执行过程。这些研究将使我们能够系统地识别分子 参与细胞死亡执行的组分和途径及其功能机制。一些 在这些研究中发现的分子可能成为治疗药物设计的潜在靶点， 癌症或其它由不适当的凋亡引起的人类疾病。

Project summary/abstract As a normal aspect of animal development and homeostasis, programmed cell death (apoptosis) plays an essential role in maintaining the physiological balance of appropriate cell numbers by opposing uncontrolled cell proliferation. Abnormal inactivation or activation of apoptosis can lead to uncontrolled cell growth or uncontrolled cell death and may result in human diseases such as cancer, neurodegenerative diseases, and autoimmune disorders. The broad, long-term objective of this application is to understand the molecular mechanisms underlying the control and the execution of apoptosis and to use the knowledge from the study of apoptosis to facilitate development of new methods in treatment and prevention of human diseases caused by inappropriate cell death. Apoptosis is controlled and executed by an evolutionarily conserved cell death pathway. At the heart of this pathway is a family of highly specific "cell death" proteases, the caspases, which are first synthesized as inactive protease precursors and later activated through proteolysis during apoptosis. The activation of cell death proteases triggers systematic and orderly cell-disassembly of apoptotic cells and their removal by phagocytes. Several sensitized genetic screens, candidate-based reverse genetic screens, and biochemical screens have been carried out to identify CED-3 protease substrates and downstream components and pathways that trigger and coordinate the cell-disassembly and removal events. These studies have led to the identification of 20 new cell death genes and several candidate CED-3 substrates that act downstream of, or in parallel to, CED-3 to mediate various cell death execution processes, including chromosome fragmentation, mitochondria elimination, cell corpse recognition/engulfment, and other yet to be identified cell death signaling and execution events. The specific aims of this application are to: (1) characterize the functions of candidate CED-3 substrates in cell death execution; (2) identify and characterize additional genes involved in phosphatidylserine externalization, an "eat-me" signal, during apoptosis; (3) characterize genes involved in cell corpse recognition/engulfment and their acting mechanisms; and (4) characterize genes that affect other cell death execution processes. These studies should allow us to systematically identify molecular components and pathways involved in cell death execution and their functioning mechanisms. Some of the molecules identified in these studies may turn out to be potential targets for therapeutic drug designs in curing cancers or other human diseases caused by inappropriate apoptosis.