GROWTH CONTROL IN THE TESTIS AND MOLECULAR MECHANISMS OF TESTICULAR HOMEOSTASIS

睾丸生长控制和睾丸稳态的分子机制

• 批准号: 7609963
• 负责人: MARY L HIXON
• 金额: $ 9.48万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609963
• 关键词: Affect; Animals; Apoptosis; Cell Proliferation; Child; Computer Retrieval of Information on Scientific Projects Database; Cryptorchidism; Data; Development; Disease; Employee Strikes; Environment; Environmental Health; Environmental Impact; Etiology; Fetal Growth; Funding; Gene Family; Germ Cells; Grant; Growth; Homeostasis; Hypospadias; Institution; Link; Malignant neoplasm of testis; Metabolic Diseases; Molecular; Mono-S; Mus; Outcome; Pathway interactions; Play; Propylthiouracil; Research; Research Personnel; Resources; Risk; Role; Signal Pathway; Signal Transduction; Small for Gestational Age Infant; Source; Testis; Thyroid Gland; Toxic Environmental Substances; United States National Institutes of Health; base; cardiovascular risk factor; human study; in vivo; leydig interstitial cell; male; phthalate; phthalates; reproductive; reproductive development; sertoli cell; size; toxicant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Children born small for gestational age (SGA) have a significantly elevated risk of cardiovascular and metabolic diseases in adulthood; however, data is limited on how SGA may impact reproductive development. Studies indicate that altered intrauterine growth increases the risk of congenital hypospadias, cryptorchidism, and testicular cancer approximately 2- to 3- fold. Evidence for these outcomes points towards alterations in the normal function of both the Sertoli and Leydig cells. Animal and human studies suggest that impaired peri-pubertal growth can affect testis size and function into adulthood. Therefore, elucidating signaling networks which modulate testis growth and identifying environmental toxicants which impinge upon these pathways will significantly impact environmental health. Our lab focuses on the Akt1 signaling pathway and its role in maintaining peri-pubertal testicular homeostasis. We have found a striking sensitivity to germ cell apoptosis in vivo in the testis of Akt1-deficient mice exposed to mono-2- ethylhexyl-phthalate (MEHP), a peri-pubertal Sertoli cell toxicant; and a reduction in testis size and reproductive potential in mice exposed to 6-N-propylthiouracil (PTU), a thyroid toxicant which targets Sertoli cell proliferation and differentiation. Based on these findings, we hypothesize that the Akt gene family plays a critical role in peri-pubertal testis homeostasis and that toxicants which target the Sertoli cell at this developmental window provide a crucial link between the environment and the etiology of male reproductive disease.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 小于胎龄儿（SGA）出生的儿童成年后患心血管和代谢疾病的风险显著升高;然而，关于SGA如何影响生殖发育的数据有限。研究表明，子宫内生长的改变会使先天性尿道下裂、隐睾和睾丸癌的风险增加约2- 3倍。这些结果的证据表明支持细胞和间质细胞的正常功能发生了改变。动物和人类研究表明，青春期前后发育受损会影响睾丸的大小和功能，直到成年。因此，阐明调节睾丸生长的信号网络和识别影响这些途径的环境毒物将对环境健康产生重大影响。我们的实验室专注于Akt 1信号通路及其在维持青春期睾丸稳态中的作用。我们发现，暴露于青春期支持细胞毒物单-2-乙基己基邻苯二甲酸酯（MEHP）的Akt 1缺陷小鼠睾丸对体内生殖细胞凋亡具有惊人的敏感性;暴露于靶向支持细胞增殖和分化的甲状腺毒物6-N-丙基硫氧嘧啶（PTU）的小鼠睾丸大小和生殖潜力减少。基于这些研究结果，我们假设Akt基因家族在青春期睾丸内稳态中起着关键作用，并且在此发育窗口靶向支持细胞的毒物提供了环境与男性生殖疾病病因之间的关键联系。