Regulation of Cell Death Activation

描述（由申请人提供）：作为动物发育和体内平衡的正常方面，程序性细胞死亡（凋亡）通过对抗不受控制的细胞增殖在维持适当细胞数量的生理平衡方面发挥重要作用。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不受控制的细胞死亡，并可导致人类疾病，如癌症、神经退行性疾病和自身免疫性疾病。本申请的广泛、长期目标是了解细胞凋亡激活的分子机制，并利用来自细胞凋亡研究的知识来促进治疗和预防由不适当的细胞凋亡引起的癌症和其他人类疾病的新方法的开发。细胞凋亡是由进化上保守的细胞死亡途径控制和执行的。在这一途径的核心是一个高度特异性的“细胞死亡”蛋白酶家族，即半胱天冬酶，其首先作为潜在的前体或酶原合成，然后由称为溶酶体的专门机制激活。半胱天冬酶的激活启动细胞杀伤并拮抗细胞生长以维持适当的细胞数量。重要的是，发现凋亡小体和半胱天冬酶激活的正调控因子和负调控因子分别充当肿瘤抑制基因和癌基因，表明凋亡调控因子在致癌转化中的关键作用。遗传学和蛋白质组学方法的组合已被用于鉴定新的凋亡调节因子和信号传导机制。一项遗传筛选已经确定了三个新的基因，它们介导了CED-4的易位，CED-4是C。elegans细胞凋亡过程中从线粒体到核膜的变化，并可能定义新的凋亡信号机制。同时，蛋白质组学分析已经鉴定了几种有希望的CED-4结合蛋白，它们是CED-4溶酶体的潜在调节剂。本申请的具体目的是：（1）鉴定、表征和克隆介导凋亡CED-4易位的基因;（2）从蛋白质组学分析中遗传和表型地表征CED-4结合蛋白;（3）进行细胞死亡激活的生物化学和机制分析。这些系统的遗传学、生物化学和细胞生物学分析将导致识别参与凋亡激活的新基因、信号传导机制和途径。在这些研究中鉴定的一些分子可能成为治疗药物设计的潜在靶点，用于治疗由不适当的细胞凋亡引起的癌症或其他人类疾病。 公共卫生相关性：细胞程序性死亡（凋亡）通过维持适当的细胞数量在动物发育和组织稳态中起着重要作用。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不受控制的细胞死亡，并可导致人类疾病，如癌症、神经退行性疾病和自身免疫性疾病。本申请的广泛、长期目标是了解控制细胞凋亡激活的分子机制，并使用来自这些研究的知识来促进治疗和预防由不适当的细胞凋亡引起的癌症和其他人类疾病的新方法的开发。细胞凋亡是由进化上保守的高度特异性的“细胞死亡”蛋白酶家族，半胱天冬酶控制和执行的。细胞死亡半胱天冬酶的激活由一个多蛋白质复合物命名为磷脂酶体触发细胞杀伤和拮抗不受控制的细胞生长。正性和负性的调节因子，半胱天冬酶激活被发现作为肿瘤抑制基因和癌基因，分别。我们已经使用遗传学和生物化学方法来鉴定调节染色体组装、活性和定位的蛋白质，并可能定义新的肿瘤抑制基因和癌基因。在这些研究中鉴定的一些分子可能成为治疗药物设计的潜在靶点，用于治疗由不适当的细胞凋亡引起的癌症或其他人类疾病。

DESCRIPTION (provided by applicant): 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 activation of apoptosis and to use the knowledge from the study of apoptosis to facilitate development of new methods in treatment and prevention of cancers and other human diseases caused by inappropriate apoptosis. 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 latent precursors or zymogens and later activated by specialized machinery named apoptosome. The activation of caspases initiates cell killing and antagonizes cell growth to maintain appropriate cell numbers. Importantly, both positive and negative regulators of apoptosome and caspase activation are found to act as tumor suppressor genes and oncogenes, respectively, indicating crucial roles of apoptosis regulators in oncogenic transformation. A combination of genetic and proteomic approaches have been carried out to identify new apoptosis regulators and signaling mechanisms. A genetic screen has identified three new genes that mediate the translocation of CED-4, a central component of the C. elegans apoptosome, from mitochondria to nuclear membrane during apoptosis, and may define new apoptosis signaling mechanisms. In parallel, a proteomic analysis has identified several promising CED-4-binding proteins that are potential regulators of the CED-4 apoptosome. The specific aims of this application are to: (1) identify, characterize and clone genes that mediate apoptotic CED-4 translocation; (2) characterize genetically and phenotypically CED-4-binding proteins from proteomic analysis; (3) perform biochemical and mechanistic analyses of cell death activation. These systematic genetic, biochemical, and cell biological analyses will lead to identification of new genes, signaling mechanisms, and pathways involved in apoptosis activation. 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. PUBLIC HEALTH RELEVANCE: Programmed cell death (apoptosis) plays an essential role in animal development and tissue homeostasis by maintaining appropriate cell numbers. 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 controlling the activation of apoptosis and to use the knowledge from these studies to facilitate development of new methods in treatment and prevention of cancer and other human diseases caused by inappropriate apoptosis. Apoptosis is controlled and executed by an evolutionarily conserved family of highly specific "cell death" proteases, the caspases. The activation of cell death caspases by a multi-protein complex named apoptosome triggers cell killing and antagonizes uncontrolled cell growth. Positive and negative regulators of apoptosome and caspase activation are found to act as tumor suppressor genes and oncogenes, respectively. We have used both genetic and biochemical methods to identify proteins that regulate the assembly, the activity and the localization of the apoptosome and may define new tumor suppressor genes and oncogenes. 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.