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

项目总结/摘要 在这个NIH F31 NRSA奖学金提案中，我提出了一个研究和培训计划， 内分泌学、微生物学和生物信息学。Varykina Thackray博士（加州大学圣地亚哥分校的导师）， 生殖内分泌学专家Scott Kelley博士（圣地亚哥州立大学联合导师）， 微生物多样性和生物信息学，将监督我的研究和职业发展。我的训练将包括 密集的研究经验，在科学传播，伦理学和 研究设计，并获得职业技能，这将有助于我成为一个独立的生物医学 研究员我的建议集中于阐明青春期在肠道成熟中的作用 微生物组虽然对人类和啮齿动物的研究表明， 在前青春期和成年期之间的变化，以性别特异性的方式，通过这种机制， 青春期调节肠道微生物组的机制尚不清楚。性类固醇由肝脏和肠道的一个子集结合 微生物能够代谢结合的性类固醇。因此，青春期可能直接调节生长 通过为特定微生物提供能量来源（性类固醇）来控制肠道微生物组的组成。我 初步数据表明，青春期前肠道微生物和代谢物的组成发生变化后， 这一结果支持了青春期可能促使性别特异性肠道微生物组成熟的观点。 我假设青春期通过性类固醇调节肠道微生物来驱动肠道微生物组的性别特异性成熟。 细菌生长和代谢产物产生。在目标1中，我将确定青春期对发育的影响， 使用Gnrh 1hpg小鼠模型的性别特异性肠道微生物组。因为这个模型不经历青春期， 这将允许识别肠道微生物群和代谢组中的青春期和性别特异性变化。我 还将确定性类固醇是否在青春期期间驱动肠道微生物组的性别特异性成熟， 性腺切除术和类固醇激素替代在青春期C57 BL/6小鼠。在目标2中，我将确定 性类固醇是否可以通过确定是否有来自术后的粪浆来对肠道微生物产生直接影响， 青春期小鼠代谢结合的性类固醇。我还将测试性类固醇是否由特定的代谢 我在目标1中确定的与青春期有关的微生物。此外，我将决定是否 性类固醇的存在改变了粪浆的微生物群落组成， 青春期后的状态鉴于许多肠道微生物群相关疾病，如糖尿病，多囊 卵巢综合征和抑郁症，表现在青春期，了解青春期如何塑造肠道 微生物组可能对解释这些疾病的病因和病理学很重要。

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.