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ACTIVATION OF CELL SUICIDE IN THE IMMUNE SYSTEM

免疫系统中细胞自杀的激活

基本信息

批准号：
6490018
负责人：
DAVID S UCKER
金额：
$ 27.11万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-01 至 2003-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6490018
关键词：
T lymphocyte apoptosis autoimmunity cyclin dependent kinase cyclins cysteine endopeptidases enzyme activity enzyme inhibitors laboratory mouse phagocytes phagocytosis protein localization tissue /cell culture transfection

项目摘要

Cell death serves a critical physiological process in organismal development and in homeostasis. In particular, it plays a pivotal role in shaping and maintaining a non-autoreactive and self-limiting immune repertoire. We have addressed the fundamental question of whether a common cell-autonomous effector mechanism pertains in distinct cases of lymphocyte cell death. We have examined death-associated events in different cell death responses in different lymphocyte cell lines, and we have exploited death-inhibitory gene products to map the order of action of the associated activities. This work has led to the identification of a thematically conserved, ordered pathway. We have defined operationally a point of death commitment by distinguishing necessary but non-lethal [modulatory] steps from those [effector] steps which cannot be dissociated from actual death. Remarkably, the requisite activities of caspases (the family of death-associated cysteine proteases), functioning in a cascade punctuated by Bcl-2, map to the modulatory phase of the process, while cyclin dependent kinase (Cdk) activity, normally associated with cell division, plays a critical role in the effector phase of cell death. Caspases serve to activate resident Cdk components. Genetic interference with caspase- dependent Cdk complexes does not alter caspase activity or other upstream events, including mitochondrial depolarization, yet it spares cells from death. The experiments proposed seek to refine this operational characterization of Cdk function through molecular, biochemical, and cellular analyses, and to identify the critical targets of lethal Cdk action. The ability of a dying cell to trigger phagocytosis without eliciting an inflammatory response likely is the overriding biological purpose of the physiological cell death process. We will extend our characterization of the caspase- and Cdk-dependent pathway of cell death with respect to the order of events involved in inducing non-inflammatory engulfment of dying cells. Just as we employed inhibitory gene products to distinguish modulatory and effector steps of the process leading to the loss of cellular integrity, we will dissect events that lead to appropriate recognition and clearance by phagocytic cells. An understanding of the regulation, mechanism, and outcome of the physiological cell death process will offer insights to normal cell and tissue development, and may provide new views of aging and treatments for pathological conditions, including autoimmune diseases and cancers.

细胞死亡是生物体发育和体内平衡的重要生理过程。特别是，它在形成和维持非自身反应性和自限性免疫库中起关键作用。我们已经解决了一个共同的细胞自主效应机制是否属于淋巴细胞死亡的不同情况下的基本问题。我们已经研究了死亡相关的事件在不同的细胞死亡反应在不同的淋巴细胞系，我们已经利用死亡抑制基因产物映射的行动顺序的相关活动。这项工作导致了一个主题保守的，有序的途径的鉴定。我们已经在操作上定义了一个死亡承诺点，通过区分必要的但非致命的[调节性]步骤和那些不能与实际死亡分离的[效应器]步骤。值得注意的是，在Bcl-2间断的级联中起作用的半胱天冬酶（死亡相关半胱氨酸蛋白酶家族）的必要活性映射到该过程的调节阶段，而通常与细胞分裂相关的细胞周期蛋白依赖性激酶（Cdk）活性在细胞死亡的效应阶段中起关键作用。半胱天冬酶用于激活常驻Cdk组分。对半胱天冬酶依赖性Cdk复合物的遗传干扰不改变半胱天冬酶活性或其他上游事件，包括线粒体去极化，但它使细胞免于死亡。提出的实验试图通过分子、生物化学和细胞分析来完善Cdk功能的操作特征，并确定致命Cdk作用的关键靶点。垂死细胞触发吞噬作用而不引发炎症反应的能力可能是生理性细胞死亡过程的首要生物学目的。我们将扩展我们的特性的caspase-和Cdk-依赖的细胞死亡的途径，相对于诱导非炎症性吞噬垂死细胞的事件的顺序。正如我们采用抑制性基因产物来区分导致细胞完整性丧失的过程的调节和效应步骤一样，我们将剖析导致吞噬细胞适当识别和清除的事件。对生理性细胞死亡过程的调控、机制和结果的理解将为正常细胞和组织发育提供见解，并可能为衰老和病理条件（包括自身免疫性疾病和癌症）的治疗提供新的观点。