Nonapoptotic roles for proteases in spermatogenesis

蛋白酶在精子发生中的非凋亡作用

• 批准号: 7336280
• 负责人: BRUCE A HAY
• 金额: $ 27.02万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336280
• 关键词: Address; Affect; Animals; Apoptosis; Apoptosis Promoter; Apoptotic; Caspase; Cell Death; Cell membrane; Cells; Cessation of life; Cleaved cell; Condition; Cytoplasm; Disease; Drosophila genus; Employee Strikes; Endopeptidases; Enzyme Precursors; Family; Fertility; Genes; Giant Cells; Goals; Haploidy; Health; Human; Infertility; Lead; Mammals; Mediating; Mutation; Numbers; Pathway interactions; Peptide Hydrolases; Phagocytosis; Process; Proteins; Reporting; Research Personnel; Role; Signal Pathway; Signal Transduction; Spermatids; Spermatogenesis; Sterility; Thinking; Work; apoptotic protease-activating factor 1; caspase-2; caspase-3; caspase-7; caspase-9; cell type; design; fly; insight; male; mutant; novel; research study; response; sperm cell; ward

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）：整个动物界的精子是在种系合胞菌中产生并成熟的。单倍体合成精子分化为单运动精子需要将每个精子封装在一个独立的质膜内，并消除大多数精子细胞质，这是一种称为个性化的过程。关于如何实现个性化的知之甚少。但是，这一过程的一个方面对人类生育的重要性，消除了多余的细胞质，这表明了以下事实：许多情况或治疗导致不孕症破坏了这一过程。 我们最近报道说，果蝇中的精子个性化需要多种caspase家族蛋白酶及其活化剂。这些观察结果令人震惊，因为胱天蛋白酶是进化保守的凋亡细胞死亡机的核心。一旦激活，它们通常会切割许多细胞底物，这些细胞底物最终导致细胞死亡和尸体吞噬作用。我们的观察结果提出了许多问题，特别是1）在存在活跃的胱天蛋白酶的存在下会诱发其他细胞凋亡的活性胱天蛋白酶，如何避免精子死亡？ 2）介导精子中caspase激活的途径是什么？ 我们提出了三个特定的目的来解决这些问题。我们将：1）表征精子在存在激活caspase的情况下避免凋亡的机制； 2）确定介导精子中caspase激活的机制；最后，3）我们将表征来自雄性无菌蝇的最新大规模筛查的突变，其目的是识别caspase活性的新调节剂和精子发生中的功能。在研究的地方，苍蝇和哺乳动物中的信号通路利用类似的组件和调节机制。因此，拟议的实验成功完成可能会增加我们对在人类健康和疾病中如何调节精子发生的理解。此外，这项工作可能会洞悉caspase活性的机制以及caspase激活的后果。