Molecular and Genetic Control of Programmed Cell Death

程序性细胞死亡的分子和遗传控制

• 批准号: 8725677
• 负责人: John M Abrams
• 金额: $ 39.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725677
• 关键词: Acquired Immunodeficiency Syndrome; Adaptor Signaling Protein; Affect; Aging; Animals; Apical; Apoptosis; Apoptotic; Biochemical; Blood Cells; Cardiovascular Diseases; Caspase; Cell Death; Cells; Cessation of life; Clinic; Complex; Degenerative Disorder; Dendrites; Development; Diagnosis; Disease; Drosophila genus; Enzymes; Exhibits; Future; Genetic; Genetic Models; Grant; Health; Heart; Heart Diseases; Hematopoiesis; Holoenzymes; Human; Immunity; In Vitro; Insecta; Knowledge; Lead; Link; Malignant Neoplasms; Mammals; Mediating; Modeling; Molecular; Molecular Genetics; Molecular Machines; Mus; Mutation; Nervous System Physiology; Neurodegenerative Disorders; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Physiological; Positioning Attribute; Process; Property; Proteins; Recruitment Activity; Regulation; Research; Signal Transduction; Specific qualifier value; Supporting Cell; Synapses; Synaptic plasticity; System; Testing; Time; Tissues; To specify; Virus Diseases; Work; apoptotic protease-activating factor 1; biological systems; caspase-7; caspase-9; cell injury; cell killing; cell motility; cell suicide; cell type; fly; genetic variant; human disease; in vitro activity; in vivo; insight; killings; novel; prevent; public health relevance; response; sperm cell; tool

DESCRIPTION (provided by applicant): Apoptosis is a universal feature of normal development and aging. This form of cell death is firmly established in the pathogenesis and treatment of many human diseases, including cancer, AIDS, neurodegenerative disorders, auto-immunities and cardiovascular disease. In many ways, and despite extensive research, our knowledge of apoptotic cell death in biological systems and in the clinic is incomplete. Our research seeks a comprehensive understanding of molecular networks that support cell death in vivo using sophisticated experimental tools and unique opportunities available in the Drosophila system. Throughout the animal kingdom, a universally conserved molecular machine referred to as the apoptosome lies at the heart of apoptotic networks. In canonical models, this complex functions as a platform to launch a cascade of proteases known as caspases that, in turn, promote self-destruction. However, it is also now widely appreciated that the apoptosome does not inevitably provoke cell suicide but can, instead, also act to remodel cells, supporting a wide range of adaptive physiological functions such as hematopoiesis and synaptic plasticity. Determinants that specify whether the apoptosome acts to kill or remodel have not been identified and prevailing models do not explain how the apoptosome functions without provoking cell death. We confront these and related questions by capitalizing on Tango7, a new regulator of apoptosome-dependent cell death that we discovered in the current grant period. Tango7 is highly conserved and is one of just a few proteins that promotes apoptosome activity in vitro and is also required for caspase activity, cell death and remodeling in vivo. By leveraging this unique entry point, we integrate genetic and biochemical approaches to examine apoptosome function as it collaborates with Tango7 to support cell killing and promote cell remodeling. Our aims will advance novel determinants and general principles that control cell death and other caspase- dependent functions in vivo. Because molecular pathways governing these processes are well conserved, insights resulting from this initiative could facilitate novel rationales for the treatmnt of diseases where aberrant caspase activity and cell death are implicated.

描述（由申请人提供）：细胞凋亡是正常发育和衰老的普遍特征。这种形式的细胞死亡在许多人类疾病的发病机制和治疗中根深蒂固，包括癌症、艾滋病、神经退行性疾病、自身免疫和心血管疾病。在许多方面，尽管进行了广泛的研究，但我们对生物系统和临床中的凋亡细胞死亡的认识是不完整的。我们的研究旨在利用果蝇系统中先进的实验工具和独特的机会，全面了解支持体内细胞死亡的分子网络。在整个动物界，一个普遍保守的分子机器被称为凋亡体，位于凋亡网络的核心。在典型模型中，这种复合物作为一个平台，启动一系列称为半胱天冬酶的蛋白酶，反过来促进自我毁灭。然而，现在也广泛认识到，线粒体不一定会引起细胞自杀，而是还可以起到重塑细胞的作用，支持广泛的适应性生理功能，如造血和突触可塑性。决定性因素，具体说明是否对染色体的行为杀死或改造尚未确定和流行的模型不解释如何对染色体的功能，而不引起细胞死亡。我们通过利用Tango7来解决这些问题和相关问题，Tango7是我们在当前资助期间发现的一种新的依赖于细胞死亡的调节因子。Tango7是高度保守的，是少数几种在体外促进溶酶体活性的蛋白质之一，也是体内半胱天冬酶活性、细胞死亡和重塑所必需的。通过利用这种独特的 作为一个切入点，我们整合了遗传和生化方法来研究线粒体功能，因为它与Tango7合作支持细胞杀伤和促进细胞重塑。我们的目标将推进新的决定因素和一般原则，控制细胞死亡和其他半胱天冬酶依赖的功能在体内。由于控制这些过程的分子途径是保守的，因此从这一倡议中获得的见解可能有助于治疗涉及异常胱天蛋白酶活性和细胞死亡的疾病的新理论。