Regulation of Cell Death Activation

描述(申请人提供)：作为动物发育和动态平衡的一个正常方面，细胞程序性死亡(细胞凋亡)通过反对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着至关重要的作用。细胞凋亡的异常失活或激活可导致细胞生长失控或细胞死亡失控，并可能导致癌症、神经退行性疾病和自身免疫性疾病等人类疾病。这一应用的广泛、长期的目标是了解激活细胞凋亡的分子机制，并利用细胞凋亡研究中的知识来促进开发新的方法来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。细胞凋亡是由进化上保守的细胞死亡途径控制和执行的。该途径的核心是一类高度特异的“细胞死亡”蛋白，即caspase，它们首先被合成为潜在的前体或酵素，然后被称为凋亡体的特殊机械激活。半胱氨酸天冬氨酸氨基转移酶的激活启动细胞杀伤，并抑制细胞生长以维持适当的细胞数量。重要的是，凋亡体和caspase激活的正调控因子和负调控因子分别作为抑癌基因和癌基因被发现，表明凋亡调控因子在致癌转化中起着至关重要的作用。已经开展了遗传学和蛋白质组学相结合的方法来识别新的细胞凋亡调节因子和信号机制。基因筛查已经发现了三个新的基因，它们介导了线虫凋亡体的中心成分CED-4在细胞凋亡过程中从线粒体到核膜的移位，并可能定义新的凋亡信号机制。与此同时，蛋白质组学分析已经确定了几个有希望的CED-4结合蛋白，它们是CED-4凋亡体的潜在调节蛋白。这一应用的具体目的是：(1)识别、表征和克隆介导CED-4易位的基因；(2)从蛋白质组学分析中确定CED-4结合蛋白的基因和表型；(3)进行细胞死亡激活的生化和机制分析。这些系统的遗传、生化和细胞生物学分析将导致识别参与细胞凋亡激活的新基因、信号机制和途径。这些研究中确定的一些分子可能成为治疗癌症或其他由不适当的细胞凋亡引起的人类疾病的治疗药物设计的潜在靶点。 公共卫生相关性：程序性细胞死亡(细胞凋亡)通过维持适当的细胞数量，在动物发育和组织动态平衡中起着至关重要的作用。细胞凋亡的异常失活或激活可导致细胞生长失控或细胞死亡失控，并可能导致癌症、神经退行性疾病和自身免疫性疾病等人类疾病。这一应用的广泛、长期的目标是了解控制细胞凋亡激活的分子机制，并利用这些研究的知识促进开发新的方法来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。细胞凋亡是由进化上保守的高度特异的“细胞死亡”蛋白--半胱氨酸酶家族控制和执行的。一种名为凋亡体的多蛋白复合体激活细胞死亡半胱氨酸天冬氨酸酶，触发细胞死亡，并拮抗失控的细胞生长。细胞凋亡体和半胱氨酸天冬氨酸氨基转移酶激活的正调控因子和负调控因子分别作为肿瘤抑制基因和癌基因。我们已经使用遗传和生化方法来鉴定调节凋亡体的组装、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。这些研究中确定的一些分子可能成为治疗癌症或其他由不适当的细胞凋亡引起的人类疾病的治疗药物设计的潜在靶点。

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.