AGOLGA3, A PROTEIN ESSENTIAL FOR SPERMATOGENESIS

AGOLGA3，精子发生必需的蛋白质

• 批准号: 8359752
• 负责人: CAROL C LINDER
• 金额: $ 11.22万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359752
• 关键词: Affect; Apoptosis; Biomedical Research; Cells; Defect; Development; Exhibits; Exons; Funding; Genes; Germ Cells; Goals; Golgi Apparatus; Grant; Human Identifications; Induced Mutation; Infertility; Male Infertility; Meiosis; Mus; Mutant Strains Mice; Mutation; National Center for Research Resources; New Mexico; Nonsense Codon; Pathway interactions; Point Mutation; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Role; Source; Sperm Head; Sperm Tail; Spermatogenesis; Stem cell transplant; Testis; United States National Institutes of Health; Western Blotting; cell type; cost; human male; male; member; protein expression; protein transport; research study; sertoli cell; sperm cell

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of my research is to identify mechanisms responsible for sperm differentiation using mice to understand normal development and aid in the treatment of human male infertility. Mice with the repro27 chemically-induced mutation display male-specific infertility characterized by cell dealth in late meiosis and abnormal differentiatiion leading to abnormal sperm heads and tails. repro27 mice have a point mutation in the golgin subfamily A member 3 (Golga3) gene that inserts a premature stop codon in exon 18. Protein expression analysis using Western blotting suggests that GOLGA3 protein is degraded in mutant mice. GOLGA3 is a Golgi complex protein implicated in protein trafficking of certain proteins, apoptosis, and spermatogenesis. GOLGA3 is expressed in both somatic Sertoli cells and germ cells but its function is not known. The objective of this proposal is to understand GOLGA3's role in spermatogenesis by utilizing repro27 mutant mice known to carry a mutation in this gene. The central hypothesis is that repro27 mutant mice exhibit multiple spermatogenesis defects resulting from disrupted GOLGA3-dependent pathways. Although Golga3 mutations have not been identified in humans, identification of affected genes and pathways may be conserved. Thus, repro27 mice will be used to 1) conduct spermatogonial stem cell transplant experiments to determine if GOLGA3 function is germ cell specific; and 2) study the role of GOLGA3 in the testis at transcriptional and post-translational levels. Spermatogenesis in reciprocal stem cell transplant experiments will be used to determine cell type requirements. Validated protein targets and demonstrated protein interactions will dissect GOLGA3 pathways. Results will facilitate our understanding of spermatogenesis and may provide new clues and treatment options for human male infertility.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我的研究的总体目标是利用小鼠来确定负责精子分化的机制，以了解正常发育并帮助治疗人类男性不育症。具有rep 27化学诱导突变的小鼠表现出雄性特异性不育，其特征在于减数分裂晚期的细胞死亡和异常分化，导致异常的精子头部和尾部。 rep 27小鼠在Golgin亚家族A成员3（Golga 3）基因中具有点突变，其在外显子18中插入提前终止密码子。蛋白质表达分析表明，GOLGA 3蛋白在突变小鼠中降解。GOLGA 3是一种高尔基复合体蛋白，参与某些蛋白质的蛋白质运输、细胞凋亡和精子发生。GOLGA 3在体细胞支持细胞和生殖细胞中表达，但其功能尚不清楚。该提案的目的是通过利用已知携带该基因突变的repro 27突变小鼠来了解GOLGA 3在精子发生中的作用。核心假设是，rep 27突变小鼠表现出多种精子发生缺陷，这是由于GOLGA 3依赖性途径被破坏所致。虽然Golga 3突变尚未在人类中发现，但受影响的基因和途径的鉴定可能是保守的。因此，rep 27小鼠将用于1）进行精原干细胞移植实验以确定GOLGA 3功能是否是生殖细胞特异性的;和2）在转录和翻译后水平研究GOLGA 3在睾丸中的作用。将使用相互干细胞移植实验中的精子发生来确定细胞类型要求。经验证的蛋白质靶点和经证实的蛋白质相互作用将剖析GOLGA 3途径。研究结果将有助于我们对精子发生的理解，并可能为人类男性不育提供新的线索和治疗方案。