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: 8601403
• 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/8601403
• 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; Genetic Variation; 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; 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(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得到了牢固的确立，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了解是不完整的。我们的研究使用先进的实验工具和果蝇系统中提供的独特机会，寻求对支持体内细胞死亡的分子网络的全面了解。在整个动物界，一种被称为凋亡体的普遍保守的分子机器位于凋亡网络的核心。在经典模型中，这种复合体的作用是作为一个平台，启动一系列被称为半胱氨酸天冬氨酸酶的蛋白水解酶，进而促进自我毁灭。然而，现在也被广泛认识到，凋亡体并不必然导致细胞自杀，相反，它也可以重塑细胞，支持广泛的适应性生理功能，如造血和突触可塑性。指定凋亡体是杀死还是重塑的决定因素尚未确定，目前流行的模型也无法解释凋亡体如何在不引起细胞死亡的情况下发挥作用。我们通过利用Tango7来应对这些和相关的问题，Tango7是我们在当前的赠款期间发现的一种新的凋亡体依赖性细胞死亡调节因子。Tango7高度保守，是为数不多的在体外促进凋亡体活性的蛋白质之一，也是体内caspase活性、细胞死亡和重塑所必需的。通过利用这一独特的 作为切入点，我们集成了遗传和生化方法来检测凋亡体的功能，因为它与Tango7合作支持细胞杀伤和促进细胞重塑。我们的目标将推动在体内控制细胞死亡和其他caspase依赖功能的新决定因素和一般原则。由于控制这些过程的分子途径非常保守，这一倡议产生的见解可能有助于治疗与caspase活性异常和细胞死亡有关的疾病的新理论。