Investigating the Role of Puberty in the Sex-Specific Maturation of the Gut Microbiome

项目摘要/摘要 在这份NIH F31 NRSA奖学金提案中，我提出了一个研究和培训计划，该计划将生殖 内分泌学、微生物学和生物信息学。瓦利金娜·萨克雷博士(加州大学圣地亚哥分校的导师)是 生殖内分泌学和斯科特·凯利博士(圣地亚哥州立大学的共同导师)， 微生物多样性和生物信息学，将监督我的研究和职业发展。我的培训将包括 有深入的研究经验，在科学交流、伦理学和 研究设计和职业技能的获得将帮助我成为一名独立的生物医学人员 研究员。我的建议集中在阐明青春期在肠道成熟中的作用。 微生物组。而对人类和啮齿动物的研究表明，肠道微生物群的组成 青春期前和成年期之间特定性别的变化，通过什么机制 青春期调节肠道微生物群未知。性类固醇是由肝脏和肠道的一部分结合的 微生物能够代谢结合性类固醇。因此，青春期可能直接调节生长发育 并通过为特定微生物提供能量来源(性类固醇)来组成肠道微生物群。我的 初步数据显示，青春期前肠道微生物和代谢物的组成在 雌性小鼠的青春期，支持青春期可能推动性别特定的肠道微生物群成熟的观点。 我假设青春期通过性激素对肠道的调节来驱动肠道微生物群的性别特异性成熟。 细菌生长和代谢产物的产生。在目标1中，我将确定青春期对发育的影响 使用Gnrh1hpg小鼠模型对性别特定的肠道微生物组进行了研究。由于这种模式不会经历青春期， 这将允许确定肠道微生物区系和代谢组中青春期和性别的特定变化。我 还将确定在青春期使用性激素是否会驱动肠道微生物组的性别特异性成熟 C57BL/6小鼠青春期性腺切除和类固醇激素替代。在目标2中，我将确定 性类固醇是否能通过确定粪便浆液是否来自后肠道微生物而直接影响肠道微生物 青春期小鼠代谢结合性类固醇。我还将测试性类固醇是否由特定的 我在目标1中发现的与青春期有关的微生物。此外，我将确定是否 性类固醇的存在将粪便浆液的微生物群落组成从青春期前的小鼠转移到 青春期后的状态。鉴于许多肠道微生物组相关疾病，如糖尿病、多囊 卵巢综合症和抑郁症在青春期表现出来，了解青春期如何塑造肠道 微生物组在破译这些疾病的病因学和病理学方面可能很重要。

Project Summary/Abstract In this NIH F31 NRSA Fellowship proposal, I present a research and training program that integrates reproductive endocrinology, microbiology, and bioinformatics. Dr. Varykina Thackray (Mentor at UC San Diego), an expert in reproductive endocrinology, and Dr. Scott Kelley (Co-Mentor at San Diego State University), an expert in microbial diversity and bioinformatics, will oversee my research and career development. My training will include an intensive research experience, didactic and informal instruction in scientific communication, ethics, and research design, and acquisition of career skills that will help me to become an independent biomedical researcher. My proposal focuses on elucidating the role of puberty in the maturation of the intestinal (gut) microbiome. While studies in humans and rodents have shown that the composition of the gut microbiome changes between pre-adolescence and adulthood in a sex-specific manner, the mechanisms through which puberty regulates the gut microbiome are unknown. Sex steroids are conjugated by the liver, and a subset of gut microbes are able to metabolize conjugated sex steroids. Therefore, puberty may directly regulate the growth and composition of the gut microbiome by providing an energy source (sex steroids) for specific microbes. My preliminary data demonstrates that the composition of pre-pubescent gut microbes and metabolites shifts after puberty in female mice, supporting the idea that puberty may drive maturation of the sex-specific gut microbiome. I hypothesize that puberty drives sex-specific maturation of the gut microbiome via sex steroid regulation of gut bacterial growth and metabolite production. In Aim 1, I will determine the effect of puberty on the development of the sex-specific gut microbiome using the Gnrh1hpg mouse model. Since this model does not undergo puberty, this will allow the identification of both pubertal- and sex-specific changes in gut microbiota and metabolome. I will also determine whether sex steroids drive sex-specific maturation of the gut microbiome during puberty using gonadectomy and steroid hormone replacement during puberty in C57BL/6 mice. In Aim 2, I will ascertain whether sex steroids can exert direct effects on gut microbes by determining whether fecal slurries from post- pubertal mice metabolize conjugated sex steroids. I will also test whether sex steroids are metabolized by specific microbes that I identify in Aim 1 as being associated with puberty. Additionally, I will determine whether the presence of sex steroids shifts the microbial community composition of fecal slurries from pre-pubertal mice to a post-pubertal-like state. Given that many gut microbiome-associated diseases, such as diabetes, polycystic ovary syndrome, and depression, manifest during puberty, understanding how puberty shapes the gut microbiome may be important in deciphering the etiology and pathology of these diseases.