Regulation of Cell Death Activation

细胞死亡激活的调节

基本信息

批准号：
8469517
负责人：
DING XUE
金额：
$ 26.59万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-19 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469517
关键词：
Affect Animals Apoptosis Apoptosis Regulator Apoptotic Autoimmune Diseases BCL2 gene Binding Binding Proteins Biochemical Biological Biological Assay Caenorhabditis elegans Caspase Cell Count Cell Death Cell Proliferation Cell physiology Cells Chromosome Mapping Cloning Co-Immunoprecipitations Complex Defect Development Disease Drug Design Enzyme Precursors Equilibrium Event Family Gene Mutation Genes Genetic Genetic Screening Heart Homeostasis Homologous Gene Human In Vitro Knowledge Lead Location Malignant Neoplasms Mass Spectrum Analysis Mediating Methods Mitochondria Molecular Molecular Genetics Mutation Names Neurodegenerative Disorders Nuclear Envelope Oncogenes Oncogenic Organism Pathway interactions Pattern Phenotype Physiological Play Proteins Proteomics RNA Interference Regulation Role Signal Transduction Surface Tissues Tumor Suppressor Genes apoptotic protease-activating factor 1 cancer prevention cell growth cell killing cofactor dimer gene cloning genetic analysis human disease in vitro Assay in vivo inhibitor/antagonist insight loss of function overexpression prevent protein complex public health relevance receptor research study therapeutic target uncontrolled cell growth

项目摘要

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.

描述（由申请人提供）：作为动物发育和稳态的正常方面，程序性细胞死亡（凋亡）在通过反对不受控制的细胞增殖来维持适当细胞数量的生理平衡中起着至关重要的作用。异常的失活或凋亡激活会导致细胞生长或不受控制的细胞死亡，并可能导致人类疾病，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，长期的目标是了解凋亡激活的分子机制，并利用细胞凋亡研究中的知识来促进在治疗和预防癌症和其他由不适当凋亡引起的癌症和其他人类疾病的发展。凋亡由进化保守的细胞死亡途径控制和执行。该途径的核心是一个高度特定的“细胞死亡”蛋白酶的家族，caspase首先合成为潜在前体或Zymogens，后来被称为凋亡小体的专用机械激活。胱天蛋白酶的激活引发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，发现凋亡组和胱天蛋白酶激活的阳性和阴性调节剂分别充当肿瘤抑制基因和致癌基因，表明凋亡调节剂在致癌转化中的关键作用。已经进行了遗传学方法和蛋白质组学方法的结合，以鉴定新的凋亡调节剂和信号传导机制。一个遗传筛选已经确定了三个新的基因，这些基因介导了秀丽隐杆线虫凋亡组的CED-4的易位，从线粒体到凋亡过程中的核膜，并可能定义了新的细胞凋亡信号传导机制。同时，蛋白质组学分析已经确定了几种有前途的CED-4结合蛋白，它们是CED-4凋亡组的潜在调节剂。该应用的具体目的是：（1）识别介导凋亡CED-4易位的特征和克隆基因；（2）从蛋白质组学分析中表征遗传和表型CED-4结合蛋白；（3）对细胞死亡激活进行生化和机械分析。这些系统的遗传，生化和细胞生物学分析将导致鉴定新基因，信号传导机制以及涉及凋亡激活的途径。这些研究中发现的一些分子可能是固化癌症或其他由不适当凋亡引起的治疗药物设计的潜在靶标。