Biology of the ErbB Gene Family in Spermatogonial Development

ErbB 基因家族在精原细胞发育中的生物学

• 批准号: 7937725
• 负责人: F. Kent Hamra
• 金额: $ 38.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937725
• 关键词: Adult; Agonist; American; Apical; Applications Grants; Behavior; Biological Preservation; Biological Process; Biology; Blood-Testis Barrier; Cell Cycle; Cellular biology; Cercopithecine Herpesvirus 1; Development; Dominant-Negative Mutation; ERBB2 gene; Endocrinology; Epithelial; ErbB4 gene; Event; Family; Fertilization; Gene Family; Genes; Genetic; Germ Cells; Goals; Health; Histologic; Hormone Receptor; Hormones; Human; In Vitro; Label; Lead; Life; Ligands; Link; Male Infertility; Maps; Medicine; Methods; Molecular; Mutation; Neuregulins; Pattern; Population; Process; Property; Rattus; Recovery; Reporting; Rodent; Role; Seminiferous tubule structure; Signal Pathway; Signal Transduction; Site; Spermatocytes; Spermatogenesis; Spermatogenic Cell; Spermatogonia; Staging; Stem Cell Development; Stem cells; Testing; Testis; Tight Junctions; Time; Transgenes; Transgenic Animals; Transgenic Organisms; Transplantation; base; cell type; contraceptive target; design; egg; erbB Genes; in vivo; male; migration; novel; receptor; reproductive; sertoli cell; sperm cell; spermatogenic epithelium structure

This project will significantly impact biology and medicine by defining molecular mechanisms that instruct stem cells within the testes to develop into sperm for the ultimate fertilization of eggs. The biological process by which stem cells in the testis continuously develop into sperm during the reproductive life of the adult male is termed Spermatogenesis. Currently, very little is known about how spermatogenesis is regulated at the level of the stem cell by hormones in our body. Therefore, the long term goals of this application will be to investigate the testicular endocrinology of the Erythoblastoma Virus B (ErbB) gene family of hormone receptors. These goals are based on new preliminary studies providing clear evidence that genes comprising the ErbB family are intimately involved in regulating spermatogonial development. We have found that distinct cell types in the testis differentially express receptor subunits encoded by four genes in the ErbB family (i.e. ErbB1, ErbB2, ErbB3 and ErbB4). Accordingly, hormones that stimulate the cellular effects of ErbBs, termed Neuregulins, are also uniquely expressed by different testis cell types. As the immediate goals of this grant application, under the American Recovery & Reinvestment Act of 2009 (ARRA), we propose two Specific Aims that focus on understanding the developmental fate of germ cells expressing the ErbB3 gene during spermatogenesis. This is because we have recently discovered ErbB3 to be specifically expressed by spermatogonial stem cells at a pivotal time when they are thought to be hormonally instructed to initiate spermatogenesis. In Specific Aim 1, we will perform key histological and cellular biology studies that will be instrumental in constructing a developmental fate map to show when spermatogonial stem cells express ErbB3. Once assembled, this fate map will illustrate at a cellular level how spermatogonial stem cells initiate the process of spermatogenesis in rodents. As another key step in this process, Specific Aim 2 will establish a novel genetic approach to systematically label rodent spermatogonial stem cells with vital fluorescent markers as a method to track their behavior before, during and after their entry into spermatogenesis. Thus, each aim focuses on progressing toward understanding the functional impact of ErbB3 to trigger a novel sub-set of spermatogonial stem cells to commence through the earliest steps in spermatogenesis

该项目将通过定义分子机制来显着影响生物学和医学 指示睾丸中的干细胞发展成精子，以最终受精。 睾丸中的干细胞在生物学过程中连续发展成精子 成年男性的生殖生活称为精子发生。目前，鲜为人知 关于如何通过体内的激素在干细胞水平上调节精子发生。 因此，本应用的长期目标是研究睾丸内分泌学 激素受体的红细胞瘤病毒B（ERBB）基因家族。这些目标是基于的 在新的初步研究中，有明确的证据表明包括ERBB家族的基因是 密切参与调节精子发育。我们发现了独特的单元 睾丸中的类型用ERBB中的四个基因编码的差异表达受体亚基 家庭（即ERBB1，ERBB2，ERBB3和ERBB4）。因此，刺激细胞的激素 ERBB的作用，称为神经结合蛋白，也由不同的睾丸细胞类型唯一表达。 作为本赠款申请的直接目标，在美国的恢复与再投资下 2009年法案（ARRA），我们提出了两个具体目标，专注于理解 在精子发生过程中表达ERBB3基因的生殖细胞的发育命运。这是 因为我们最近发现ERBB3是由精子茎特别表达的 在关键时期，当他们被认为是荷尔蒙指示启动的关键时期 精子发生。在特定目标1中，我们将进行关键的组织学和细胞生物学研究 这将有助于构建发育命运图，以显示精子何时 干细胞表达ERBB3。一旦组装，此命运图将在细胞级别说明 精子干细胞启动啮齿动物的精子发生过程。作为另一个钥匙 在此过程中，特定目标2将建立一种新型的遗传方法来系统标记 带有重要荧光标记物的啮齿动物精子干细胞作为跟踪其跟踪的方法 他们进入精子发生之前，之中和之后的行为。因此，每个目标都集中在 朝着理解ERBB3的功能影响促进触发新颖的子集的功能影响 精子干细胞通过精子发生的最早步骤开始