Caspase regulated cellular senescence

在多细胞生物体的整个生命过程中，所有类型的细胞都经历分裂、分化和死亡。这些过程对于正常发育和组织稳态是必不可少的，随着时间的推移，增加或减少细胞数量的机制失调会导致有机体衰老和疾病。该提案研究了控制细胞稳态的两种最重要机制之间的关系：程序性细胞死亡（凋亡）和程序性不可逆细胞周期停滞（衰老）。这项研究建议假设，细胞凋亡的严格调控部分是通过一个检查点机制来实现的，该机制评估了细胞凋亡机制的完整性。当这种完整IG时，或者当在不适当的环境中检测到凋亡信号时，检查点被激活并触发细胞过早衰老，作为一种先发制人的替代程序，以阻止失调的凋亡的有害后果。半胱氨酸蛋白酶（Caspases）是半胱氨酸蛋白酶家族中的一员，是细胞凋亡的主要分子执行者。初步工作表明，在体细胞中，caspase蛋白的外源性表达被检测为凋亡机制中的畸变，并提示细胞衰老程序的过早激活。这表明，在正常细胞中，内源性半胱天冬酶具有重要但尚未被认识到的功能，当受到干扰时，会导致衰老。该建议旨在从分子水平研究细胞凋亡调控中这一未探索的领域及其与细胞衰老的关系。长期目标是进一步了解衰老相关的疾病过程，并确定药物干预的新靶点。具体而言，该项目旨在：（1）对衰老调节所需的caspase活性进行功能分析。(2)描述半胱天冬酶调控衰老的蛋白质和信号通路. (3)识别和表征半胱天冬酶调节衰老所需的新蛋白质。这项研究将在哈佛医学院细胞生物学系进行，由袁俊英博士指导。袁博士是细胞凋亡领域公认的领导者，在促进医生-科学家的职业发展方面有着卓越的记录。袁博士和该部门完全致力于申请人的发展成为一个完全独立的临床医生，科学家在医学上重要的领域的衰老和细胞衰老。

Throughout the lives of multi-cellular organisms, cells of all types undergo periods of division, differentiation, and death. These processes are essential for normal development and tissue homeostasis, and over time, the dysregulation of mechanisms that either increase or decrease cell numbers leads to organismal aging and disease. This proposal investigates the relationship between two of the most important mechanisms that control cellular homeostasis: programmed cell death (apoptosis) and programmed irreversible cell cycle arrest (senescence). This research proposal hypothesizes that tight regulation of apoptosis is achieved in part by a checkpoint mechanism that evaluates the integrity of the apoptotic machinery. When this integrity ig lost, or when apoptosis signals are detected in inappropriate contexts, the checkpoint is activated and triggers premature cellular senescence as a pre-emptive, alternative program to thwart the deleterious consequences of dysregulated apoptosis. Caspases, a family of cysteine proteases, are the central molecular executors of apoptosis. Preliminary work suggests that in somatic cells, exogenous expression of caspase proteins is detected as an aberration in the apoptotic machinery an prompts the premature activation of the cellular senescence program. This suggests that in normal cells, endogenous caspases have an important and as yet unappreciated function, which when perturbed, leads to senescence. This proposal aims to study at the molecular level this unexplored area in apoptosis regulation and its relation to cellular senescence. The long- term goal is to further our understanding of aging-related disease processes and to identify novel targets for pharmacological intervention. Specifically, the project aims to: (1) Carry out a functional analysis of the caspase activity required for senescence regulation. (2) Characterize the proteins and signaling pathways operating in caspase- regulated senescence. (3) Identify and characterize novel proteins required for caspase-regulated senescence. The research will be conducted in the department of Cell Biology at Harvard Medical School, under the mentorship of Dr. Junying Yuan. Dr, Yuan is a recognized leader in the field of apoptosis, with an exceptional record for fostering the career development of physician- scientists. Dr. Yuan and the department are fully committed to the applicant's development into a fully independent clinician-scientist in the medically important fields of a o tosis and cellular senescence.