REGULATION AND FUNCTION OF THE STEM SPERMATOGONIA NICHE

干精原细胞生态位的调节和功能

• 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
• 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

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.

男配子的持续产生需要对分化和 茎精子的复制。这些关键过程发生在一个动态环境的利基市场中 由Sertoli细胞部分创建，该细胞与所有精子细胞相互作用的体细胞创建。到目前为止 Sertoli细胞调节茎精子分化和复制的体内机制尚未 被阐明了。既不了解Sertoli细胞的那些调节功能本身 受控。该应用的中心假设是，分化的精子生成细胞控制 Sertoli细胞的表达生长因子调节茎的分化和复制 精子。我们建议，通过调节这些生长因子的表达，分化了 精子生成细胞控制茎精子菌的功能。使用鼠标作为模型，这个 提案的重点是三个刺激茎精子生长的增长因素 在体内或体外。这些生长因子是：神经胶质细胞系得出的神经营养因子（GDNF）， 成纤维细胞生长因子2（FGF-2）和胰岛素类似生长因子1（IGF-1）。特定目的我检验假设 在体内通过Sertoli细胞对GDNF的阶段特异性表达调节的复制和分化 STEM精子和FGF-2和IGF-1在与GDNF的调节中作用 过程。特定的AIM II检验了A1型精子或更先进的假设 精子生成细胞通过Sertoli细胞调节GDNF，FGF-2和IGF-1的表达。开始定义 该调节的分子基础，我们还提出了对转录因子和 信号转导途径的成分，介导精子细胞对GDNF的影响 Sertoli细胞的表达。特定的目标III将检验以下假设，即通过 他们对Sertoli细胞的反馈控制茎精子的更新和分化。特定于阶段的基因 Sertoli细胞的表达是许多物种的公认现象，包括人类和GDNF， IGF-1和FGF-2都在人类睾丸中表达。因此，我们提出的实验得出的结果 理解某些男人不孕的生物学基础的希望。