Chromatin Degradation and Cell Clearance During Apoptosis

描述（由申请人提供）：作为动物发育和组织稳态的一个正常方面，细胞凋亡通过对抗不受控制的细胞增殖在维持适当细胞数量的生理平衡中发挥重要作用。细胞凋亡的异常失活或激活可导致不受控制的细胞生长或不受控制的细胞死亡，并可导致人类疾病，如癌症、神经退行性疾病和自身免疫性疾病。本申请的广泛和长期目标是了解细胞凋亡的控制和执行的基本机制，并利用这些研究的知识开发新的方法来治疗和预防与细胞凋亡相关的人类疾病，特别是癌症。染色体断裂是细胞凋亡的标志，也是细胞死亡的关键步骤。在细胞凋亡过程中，一组核酸酶被激活，并协同和顺序地起作用，以促进染色体DNA的片段化。在C. elegans，并发现至少在两个不同的途径和两个不同的功能位点，以促进DNA降解和清除凋亡细胞在凋亡过程中的作用。本申请的目的是在C. elegans解剖凋亡DNA降解机制，并解开调节凋亡DNA降解和凋亡细胞清除的基本分子机制。具体目标是：1）对C. elegans crn基因，以了解它们如何一起工作，以促进凋亡DNA降解; 2）识别和表征其他基因，是重要的凋亡DNA降解; 3）调查染色体断裂过程如何影响清除凋亡细胞，另一个关键的细胞死亡执行事件涉及组织重塑，抑制炎症，和调节免疫反应。对细胞凋亡过程中调控染色质降解和细胞清除的分子组成和生化机制的研究将为了解细胞死亡是如何进行的提供重要的见解，并有助于理解一般调控细胞凋亡的基本机制。

DESCRIPTION (provided by applicant): As a normal aspect of animal development and tissue homeostasis, 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 and long-term objectives of this application are to understand the basic mechanisms underlying the control and execution of apoptosis and to use knowledge from such studies to develop new methods to treat and prevent apoptosis-related human diseases, especially caner. Chromosome fragmentation is a hallmark of apoptosis and a critical step in cell death execution. During apoptosis, a battery of nucleases are activated and act cooperatively and sequentially to promote fragmentation of chromosomal DNA. Seven new cell death-related nucleases (CRN nucleases) have been identified in C. elegans and found to act in at least two distinct pathways and two different functioning sites to promote DNA degradation and clearance of apoptotic cells during apoptosis. The goal of this application is to carry out biochemical, molecglar genetic, and cell biological studies in C. elegans to dissect the apoptotic DNA degradation machinery and to unravel the basic molecular mechanisms that regulate the execution of apoptotic DNA degradation and clearance of apoptotic cells. The specific aims are: 1) to carry out biochemical, molecular genetic, and functional analyses of C. elegans crn genes to understand how they work together to promote apoptotic DNA degradation; 2) to identify and characterize additional genes that are important for apoptotic DNA degradation; 3) to investigate how the chromosome fragmentation process affects clearance of apoptotic cells, another critical cell death execution event involved in tissue remodeling, suppression of inflammation, and regulation of immune reponses. The studies of the molecular components and biochemical mechanisms that regulate chromatin degradation and cell clearance during apoptosis will provide crucial insights into how cell death is executed and should contribute to the understanding of the basic mechanisms that regulate apoptosis in general.