Nonapoptotic roles for proteases in spermatogenesis

蛋白酶在精子发生中的非凋亡作用

基本信息

批准号：
7008553
负责人：
BRUCE A HAY
金额：
$ 27.83万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2009-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Spermatozoa throughout the animal kingdom are generated and mature within a germline syncytium. Differentiation of haploid syncytial spermatids into single motile sperm requires the encapsulation of each spermatid within an independent plasma membrane and the elimination of most sperm cytoplasm, a process known as individualization. Little is known about how individualization is carried out. However, the importance of one aspect of this process for human fertility, the elimination of excess cytoplasm, is suggested by the fact that many conditions or treatments resulting in infertility disrupt this process. We recently reported that multiple caspase family proteases and their activators were required for spermatid individualization in Drosophila. These observations were striking because caspases are the core of the evolutionarily conserved, apoptotic cell death machine. Once activated they typically cleave a number of cellular substrates that ultimately lead to cell death and corpse phagocytosis. Our observations raise a number of questions, in particular, 1) How is it that spermatids avoid death in the presence of active caspases that would induce apoptosis in other cells? 2) What are the pathways that mediate caspase activation in spermatids? We have proposed three specific aims to address these questions. We will: 1) characterize the mechanisms that spermatids utilize to avoid apoptosis in the presence of activated caspase; 2) identify the mechanisms that mediate caspase activation in spermatids; and finally, 3) we will characterize mutations derived from a recent, large scale screen for male sterile flies, with the goal of identifying new regulators of caspase activity and function in spermatogenesis. Where studied, signaling pathways in flies and mammals utilize similar components and regulatory mechanisms. Therefore, it is likely that successful completion of the proposed experiments will increase our understanding of how spermatogenesis is regulated in human health and disease. In addition this work is likely to provide insight into the mechanisms by which caspase activity, and the consequences of caspase activation, are regulated.

描述（由申请人提供）：整个动物界的精子都是在种系合胞体中产生并成熟的。单倍体合胞精子细胞分化为单个活动精子需要将每个精子细胞封装在独立的质膜内并消除大多数精子细胞质，这一过程称为个体化。人们对个性化是如何进行的知之甚少。然而，这一过程的一个方面（即消除多余的细胞质）对于人类生育能力的重要性，是由许多导致不孕的情况或治疗破坏这一过程的事实表明的。我们最近报道，果蝇精子细胞个体化需要多种半胱天冬酶家族蛋白酶及其激活剂。这些观察结果令人震惊，因为半胱天冬酶是进化上保守的细胞凋亡机器的核心。一旦被激活，它们通常会裂解许多细胞底物，最终导致细胞死亡和尸体吞噬作用。我们的观察提出了许多问题，特别是，1）精子细胞如何在存在会诱导其他细胞凋亡的活性半胱天冬酶的情况下避免死亡？ 2）介导精子细胞中半胱天冬酶激活的途径是什么？我们提出了三个具体目标来解决这些问题。我们将：1）描述精子细胞在存在激活的半胱天冬酶的情况下避免细胞凋亡的机制； 2) 确定精子细胞中介导 caspase 激活的机制；最后，3）我们将表征最近对雄性不育果蝇进行的大规模筛选所产生的突变，目的是确定精子发生中半胱天冬酶活性和功能的新调节因子。研究发现，果蝇和哺乳动物的信号传导途径利用相似的成分和调节机制。因此，成功完成所提出的实验可能会增加我们对人类健康和疾病中精子发生如何调节的理解。此外，这项工作可能会深入了解 caspase 活性的调节机制以及 caspase 激活的后果。