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REGULATION AND FUNCTION OF THE STEM SPERMATOGONIA NICHE

干精原细胞生态位的调节和功能

基本信息

批准号：
8127161
负责人：
WILLIAM Wallace WRIGHT
金额：
$ 36.43万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8127161
关键词：
Biological Biological Assay Cells Coculture Techniques Data Drops Environment Feedback Fibroblast Growth Factor 2 Foundations Frequencies Gene Expression Germ Cells Growth Growth Factor Human IGF1 gene In Vitro Infertility Insulin-Like Growth Factor I Mediating Messenger RNA Mitogens Mitosis Modeling Molecular Mus Physiological Pluripotent Stem Cells Process Production Regulation Seminoma Signal Transduction Signal Transduction Pathway Somatic Cell Spermatogenesis Spermatogenic Cell Spermatogonia Staging Stem cells Testing Testis Transplantation Wild Type Mouse base cell growth cell type glial cell line derived neurotrophic factor, mouse glial cell-line derived neurotrophic factor in vivo mRNA Expression male men paracrine research study self-renewal sertoli cell spermatogenic epithelium structure stem stem cell niche transcription factor

项目摘要

The continuous production of male gametes requires the precise regulation of the differentiation and replication of stem spermatogonia. These critical processes occur in a niche that is a dynamic environment created in part by Sertoli cells, the somatic cells with which all spermatogenic cells interact. As yet, the in vivo mechanisms by which Sertoli cells regulate stem spermatogonial differentiation and replication have not been elucidated. Neither is it understood how those regulatory functions of Sertoli cells are themselves controlled. The central hypothesis of this application is that differentiated spermatogenic cells control the expression by Sertoli cells of growth factors that regulate the differentiation and replication of stem spermatogonia. We propose that by regulating expression of those growth factors, differentiated spermatogenic cells control the functioning of the stem spermatogonia niche. Using mice as a model, this proposal focuses on three growth factors that been shown to stimulate the growth of stem spermatogonia either in vivo or in vitro. These growth factors are: glial cell line derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF-2) and insulin like growth factor 1 (IGF-1). Specific Aim I tests the hypothesis that in vivo the stage-specific expression of GDNF by Sertoli cells regulates replication and differentiation of stem spermatogonia and that FGF-2 and IGF-1 act in consort with GDNF in the regulation of these processes. Specific Aim II tests the hypothesis that Type A1 spermatogonia or more advanced spermatogenic cells regulate expression of GDNF, FGF-2 and IGF-1 by Sertoli cells. To begin to define the molecular basis of this regulation, we also propose an unbiased search for transcription factors and components of signal transduction pathways that mediate the effects of spermatogenic cells on GDNF expression by Sertoli cells. Specific Aim III will test the hypothesis that differentiated spermatogenic cells by their feedback on Sertoli cells control stem spermatogonia renewal and differentiation. Stage-specific gene expression by Sertoli cells is a well-established phenomenon in many species, including humans and GDNF, IGF-1 and FGF-2 are all expressed in human testes. Therefore, results from our proposed experiments hold promise for understanding the biological basis of the infertility of some men.

雄性配子的持续产生需要精确的分化和调控