The CRES Gene in Reproduction

生殖中的 CRES 基因

• 批准号: 7282067
• 负责人: Gail A Cornwall
• 金额: $ 10.62万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282067
• 关键词: Acrosome; Acrosome Reaction; Active Sites; Address; Affect; Affinity; Alleles; Anatomy; Anterior Pituitary Gland; Antibodies; Attention; Award; Binding; Biochemistry; Biological; Biological Assay; Biological Process; Biological Testing; Breeding; Caspase; Cathepsins B; Cell Line; Cells; Cellular biology; Co-Immunoprecipitations; Complement; Consensus; Cystatins; Cysteine Protease; Cysteine Proteinase Inhibitors; Development; Disease; Educational process of instructing; Endopeptidases; Environment; Enzymes; Epididymis; Event; Exhibits; Family; Family member; Fertilization; Fertilization in Vitro; Funding; Gene Proteins; Genes; Germ Cells; Goals; Herpes zoster disease; Hormonal; Housekeeping; Human; Human Identifications; In Vitro; Infertility; Localized; Male Contraceptive Agents; Mediating; Messenger RNA; Mus; Neurosecretory Systems; Papain; Penetration; Peptide Hydrolases; Play; Process; Prohormone Convertase; Proprotein Convertase 2; Protease Inhibitor; Protein Analysis; Protein Family; Protein Overexpression; Protein Precursors; Proteins; Proteolytic Processing; Range; Reproduction; Reproductive system; Research; Role; Serine Protease; Site; Sperm Maturation; Sperm Motility; Subgroup; Testing; Tissues; Workplace; asparaginylendopeptidase; body system; cDNA Expression; career; egg; embryonic stem cell; homologous recombination; in vivo; inhibitor/antagonist; knockout gene; medical schools; member; novel; post gamma-globulins; prohormone; protein expression; protein structure; reproductive; reproductive function; research study; sperm cell; sperm function

DESCRIPTION (provided by applicant): The long-term objective of our research is to determine the role of the CRES (Cystatin-Related Epididymal Spermatogenic) protein in epididymal sperm maturation and sperm function. We have established that CRES defines a new subgroup in the family two cystatins of the cystatin superfamily of cysteine protease inhibitors. Although predicted to structurally resemble the archetype family two cystatins, we have recently demonstrated that CRES does not function as a typical cystatin. We determined that CRES does not inhibit cysteine proteases but rather is a competitive inhibitor (Ki = 25 nM) of the serine protease prohormone convertase 2 (PC2). Because PC2 is a member of a family of proteases with critical roles in the proteolytic maturation of prohormones and proproteins, we propose that CRES may be a new convertase inhibitor that mediates proteolytic processing events important for reproductive function. My short-term goals are to establish whether CRES interacts with PC2 or other convertases in vivo as well as to examine CRES as a convertase inhibitor in greater detail and specifically examine its effects on proprotein processing in cells. Other short-term goals are to examine the biological roles of CRES in vivo including its function in the sperm acrosome and fertilization. My long-term goals are to contribute to our understanding of how proproteins are activated to their mature and functional forms, specifically within spermatozoa and the epididymis, and the mechanisms by which these processes are regulated. Ultimately this may provide mechanisms to target for male contraceptive development. The RCDA, if awarded, will assist me in accomplishing my goals. Specifically, it will release me from Departmental obligations including substantial teaching in medical school gross anatomy, thereby allowing me to devote my full attention to research. In addition, with this award I will not be required to serve on additional committees both at the institutional and departmental levels. The Department of Cell Biology and Biochemistry provides a supportive environment for the development of my research career. Within the department is a large group of NIH-funded reproductive biologists who provide expertise and a collegial, interactive working environment. Also, the newly purchased mass spec will enable on site protein analysis for the studies described above. In short, the environment at TTUHSC is exceptional and will fully support my proposed studies.

描述（由申请人提供）：我们研究的长期目标是确定 CRES（胱抑素相关附睾生精）蛋白在附睾精子成熟和精子功能中的作用。我们已经确定，CRES 定义了半胱氨酸蛋白酶抑制剂半胱氨酸蛋白酶抑制剂超家族的两个半胱氨酸蛋白酶抑制剂家族中的一个新亚组。尽管预计在结构上类似于原型家族二胱抑素，但我们最近证明 CRES 并不具有典型的胱抑素功能。我们确定 CRES 不会抑制半胱氨酸蛋白酶，而是丝氨酸蛋白酶激素原转化酶 2 (PC2) 的竞争性抑制剂 (Ki = 25 nM)。由于 PC2 是蛋白酶家族的成员，在激素原和蛋白原的蛋白水解成熟中发挥关键作用，因此我们认为 CRES 可能是一种新的转化酶抑制剂，可介导对生殖功能重要的蛋白水解加工事件。我的短期目标是确定 CRES 是否在体内与 PC2 或其他转化酶相互作用，以及更详细地检查 CRES 作为转化酶抑制剂，并具体检查其对细胞中前蛋白加工的影响。其他短期目标是检查 CRES 在体内的生物学作用，包括其在精子顶体和受精中的功能。我的长期目标是帮助我们了解前蛋白如何被激活为其成熟和功能形式，特别是在精子和附睾中，以及这些过程的调节机制。最终，这可能为男性避孕药的开发提供目标机制。 RCDA 如果获得奖励，将帮助我实现我的目标。具体来说，它将使我摆脱部门义务，包括医学院大体解剖学的大量教学，从而使我能够全身心投入研究。此外，获得此奖项后，我将不需要在机构和部门级别的其他委员会中任职。细胞生物学与生物化学系为我的研究事业的发展提供了支持性的环境。该部门内有一大批由美国国立卫生研究院 (NIH) 资助的生殖生物学家，他们提供专业知识和合作、互动的工作环境。此外，新购买的质谱仪还将能够为上述研究进行现场蛋白质分析。简而言之，TTUHSC 的环境非常优越，将全力支持我提出的研究。