Regulation of Sexually Dimorphic Apoptosis

描述（由申请人提供）：作为动物发育和体内平衡的正常方面，程序性细胞死亡（凋亡）在维持适当细胞数量的生理平衡和塑造发育中的器官和组织（如神经系统和性二态生殖系统）中发挥重要作用。细胞凋亡的异常激活或失活，其可导致不受控制的细胞生长或不适当的细胞死亡，已涉及引起许多人类疾病，如癌症、神经退行性疾病、自身免疫性疾病和性障碍。本申请的广泛的长期目标是理解控制适当细胞中细胞凋亡的适当激活的基本机制，并使用来自这些研究的知识来促进对由不适当的细胞凋亡引起的人类疾病的理解，并最终开发治疗和预防与细胞凋亡相关的人类疾病的新方法。性别特异性细胞凋亡是一个古老的发育过程，产生适当的两性生殖结构，对动物物种的繁殖和繁殖至关重要。线虫C. elegans中，两组性别特异性神经元经历性别特异性凋亡，因此提供了研究性别特异性细胞死亡和细胞死亡激活调节的理想实验系统。本申请的目的是利用强大的分子遗传技术在C。elegans来描绘控制性二态细胞凋亡的信号通路，并解开控制细胞凋亡激活的基本分子机制。本申请的具体目的是：1）进行遗传筛选和分析，以鉴定和表征C.优雅的; 2）确定已鉴定的性别特异性死亡调节因子的分子身份; 3）阐明这些性别特异性死亡调节因子的功能机制。鉴于程序性细胞死亡途径在进化过程中是高度保守的，线虫性别特异性细胞死亡的调控研究应该为高等生物中性二态细胞凋亡的调控提供重要的见解，这仍然知之甚少，并应有助于了解一般调控细胞死亡激活的基本机制。

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 and in sculpting developing organs and tissues such as the nervous system and the sexually dimorphic reproductive systems. Abnormal activation or inactivation of apoptosis, which can lead to uncontrolled cell growth or inappropriate cell death, has been implicated in causing many human diseases such as cancer, neurodegenerative diseases, autoimmune disorders, and sexual disorders. The broad, long term objectives of this application are to understand the basic mechanisms that govern the appropriate activation of apoptosis in proper cells and to use knowledge from such studies to facilitate the understanding of human diseases caused by inappropriate apoptosis, and eventually, the development of new methods to treat and prevent apoptosis-related human diseases. Sex-specific apoptosis is an ancient developmental process that generates the appropriate sexually dimorphic reproductive structures essential for the reproduction and propagation of animal species. In the nematode C. elegans, two sets of sex-specific neurons undergo sex-specific apoptosis and thus present an ideal experimental system to study sex-specific cell death and the regulation of cell death activation. The goal of this application is to take advantage of the powerful molecular genetic techniques available in C. elegans to delineate the signaling pathways that control the execution of sexually dimorphic apoptosis and to unravel the basic molecular mechanisms that govern the activation of apoptosis. The specific aims of this application are: 1) to carry out genetic screens and analyses to identify and characterize regulators of sex-specific death (rsd genes) in C. elegans; 2) to determine the molecular identities of the identified regulators of sex-specific death; 3) to elucidate the functioning mechanisms of these regulators of sex-specific death. Given that the programmed cell death pathway is highly conserved during evolution, the studies of the regulation of sex-specific cell deaths in nematodes should provide crucial insights into the regulation of sexually dimorphic apoptosis in higher organisms, which remain poorly understood, and should contribute to the understanding of the basic mechanisms that regulate cell death activation in general.