Regulation of Stem Spermatogonia in the Mature Testis

成熟睾丸中精原细胞干的调节

• 批准号: 8460441
• 负责人: WILLIAM Wallace WRIGHT
• 金额: $ 38.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-20 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460441
• 关键词: Address; Adult; Affect; Affinity; Amino Acids; Bathing; Binding Sites; Biological Process; Biopsy; Cells; Collaborations; Complement; Data; Employee Strikes; Equilibrium; Evaluation; Fertility; Foundations; GDNF receptors; Germ Cells; Growth Factor; Human; Individual; Infertility; Instruction; Intrinsic factor; Kinetics; Knowledge; Maintenance; Mammals; Modeling; Mus; Mutation; Oligospermia; Organ; Phosphotransferases; Physiological; Play; Process; Production; Protein Tyrosine Kinase; Regulation; Role; Signal Transduction; Spermatogenesis; Spermatogonia; Staging; Stem cells; Testing; Testis; Transcript; Translating; Undifferentiated; adult stem cell; glial cell-line derived neurotrophic factor; hormone therapy; in vivo; inhibitor/antagonist; mRNA Expression; male; man; men; mouse model; protein expression; response; restoration; self-renewal; sertoli cell; sperm cell; spermatogenic epithelium structure; stem; stem cell differentiation

PROJECT SUMMARY (See instructions): An essential requirement for sustaining male fertility is maintaining an adequate number of stem spermatogonia, the foundation of spennatogenesis. To achieve this, when the stem cells divide, some progeny must remain stem spermatogonia while other progeny differentiate. It is obvious that the correct balance between self-renewing replication and differentiation of stem spermatogonia is crucial to male fertility, and there is indirect evidence that GDNF plays an important role in maintaining this balance in the normal mature testis. However, we known almost nothing about the in vivo regulation of this balance in the mature organ, of the specific function of GDNF in the adult testis, or if physiological changes in GDNF expression significantly affect the replication or differentiation of the stem cells. To address these critical issues, we have developed a unique mouse model that allows GDNF signaling to the stem spermatogonia to be specifically and reversibly inhibited in vivo by an ATP antagonist. Using this model, we have generated the first direct evidence that GDNF is required for maintaining the stem spermatogonial pool in a normal mature testis. Additionally, we have shown that when inhibition of GDNF signaling is reversed, the stem cells begin to rebuild the stem cell pool. Importantly, our data demonstrate that some stem spermatogonia are lost when GDNF signaling is inhibited for as little as 2 days, while other stem cells survive for up to 11 days. This suggests that factors intrinsic or extrinsic to the stem cells modulate the response to GDNF. Using this new mouse model we propose in Specific Aim 1 to define the mechanisms'responsible for the loss of stem spermatogonia upon inhibition of GDNF signaling and to detenmine why some cells are lost rapidly while others more slowly. Building on these results, we also propose to collaborate with Project 1 to determine if GDNF mRNA expression and/or stem spermatogonial numbers are significantly reduced in some oligospermic men. Specific Aim 2 studies the capacity of stem spermatogonia to repopulate the testis once their numbers are partially depleted. In doing so, we will identify the extent to which a defined number of stem spermatogonia can restore this pool and the biological processes responsible for this restoration. Additionally, in collaboration with Project 1 we will study oligospermic men who are receiving endocrine therapy to increase} sperm production in order to determine if in men who have a positive response to therapy, there is bath an increase in GDNF expression and/or an increase in numbers of stem spermatogonia. To jour knowledge, these specific aims constitute the first detailed in vivo analysis of theresponse of stem sjaermatogonia or any other adult stem cell to the inhibition and then restoration of signaling by an essbntial growth factor. We anticipate that the results from these studies will make an important contribution to the evaluation and eventually the treatment of infertile men.

项目概述（见说明）：