Targets of the Cell Death Proteases

细胞死亡蛋白酶的靶标

• 批准号: 7990166
• 负责人: DING XUE
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-25 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990166
• 关键词: Affect; Animals; Apoptosis; Apoptotic; Autoimmune Diseases; Biochemical; Biological; C. elegans genome; Caenorhabditis elegans; Candidate Disease Gene; Caspase; Cell Count; Cell Death; Cell Death Signaling Process; Cell Proliferation; Cell membrane; Cell physiology; Cells; Cessation of life; Chromosomes; Cleaved cell; DNA; Development; Drug Design; Eating; Enhancers; Enzymes; Equilibrium; Event; Excision; Family; Funding; Genes; Genetic; Genetic Screening; Heart; Homeostasis; In Vitro; Knowledge; Lead; Lipids; Malignant Neoplasms; Mediating; Methods; Mitochondria; Molecular; Molecular Genetics; Mutation; Nematoda; Neurodegenerative Disorders; Outcome; Pathway interactions; Peptide Hydrolases; Phagocytes; Phosphatidylserines; Physiological; Play; Prevention; Process; Proteins; Proteolysis; Role; Signal Pathway; Signal Transduction; Site; Suppressor Genes; System; Tissues; Yeasts; abstracting; aminophospholipid transporter; base; cell killing; cell suicide; human disease; insight; novel; phospholipid scramblase; positional cloning; programs; research study; therapeutic target; ubiquilin; uncontrolled cell growth

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.

项目摘要/摘要 作为动物发育和稳态的正常方面，程序性细胞死亡（凋亡）发挥 通过反对不受控制的细胞数量保持适当细胞数量的生理平衡的重要作用 细胞增殖。异常失活或凋亡激活可能导致不受控制的细胞生长或 不受控制的细胞死亡，可能导致人类疾病，例如癌症，神经退行性疾病和 自身免疫性疾病。该应用的广泛长期目标是了解分子 控制和凋亡的执行的基础机制，并利用研究的知识 凋亡促进在治疗和预防由人类疾病治疗和预防人类疾病中的发展 不当细胞死亡。 凋亡由进化保守的细胞死亡途径控制和执行。核心 途径是一个高度特定的“细胞死亡”蛋白酶的家族，caspases首先合成为 非活性蛋白酶前体，后来通过凋亡过程中的蛋白水解激活。细胞的激活 死亡蛋白酶会触发凋亡细胞的系统和有序的细胞隔离，并通过 吞噬细胞。几个灵敏的遗传筛选，基于候选的反向遗传筛选和生化 已经执行了筛选以识别CED-3蛋白酶底物和下游成分以及 触发和协调细胞隔离和去除事件的途径。这些研究导致了 鉴定20个新细胞死亡基因和几个候选CED-3底物，它们在下游或在 与CED-3平行，用于介导各种细胞死亡执行过程，包括染色体碎片， 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。此应用程序的具体目的是：（1）表征候选人的功能 细胞死亡执行中的CED-3底物； （2）识别并表征涉及的其他基因 凋亡期间，磷脂酰丝氨酸外在化，一种“饮食”信号； （3）表征涉及的基因 细胞尸体识别/吞噬及其作用机制； （4）表征影响其他的基因 细胞死亡执行过程。这些研究应该使我们系统地识别分子 细胞死亡执行及其功能机制涉及的组件和途径。一些 这些研究中鉴定出的分子可能是治疗药物设计的潜在靶标 癌症或其他由不适当凋亡引起的人类疾病。