The Impact of Gut Bile Acid Deconjugation on Host Fertility
肠道胆汁酸解离对宿主生育力的影响
基本信息
- 批准号:10579823
- 负责人:
- 金额:$ 4.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAndrogen ReceptorAndrogensAnimal Disease ModelsBackBacteriaBile AcidsBile fluidCirculationDataDevelopment PlansEmbryonic DevelopmentEngineeringEngraftmentEnvironmentEscherichia coliFemaleFertilityFrequenciesGoalsGonadal Steroid HormonesGonadal structureHomeostasisHypothalamic structureIn VitroInfertilityInflammationKnock-inLearning SkillMeasuresMediatingMentorsMentorshipMetabolic BiotransformationMetabolismMethodsModificationMusNatureNuclearNuclear ReceptorsOutcome StudyPathway interactionsPhysiologicalPhysiologyPublic HealthReceptor SignalingReproductionReproductive HealthReproductive PhysiologyResearchResearch PersonnelRoleSample SizeScientistSerumSignal TransductionSignaling MoleculeSourceSupplementationSystemTestingTestisTestosteroneTimeTissuesTrainingWeaningWild Type MouseWorkabsorptioncareer developmentcareer networkingcohortdesignexperimental studyfitnessgut microbesgut microbiomehost-microbe interactionshypothalamic pituitary gonadal axisimprovedinnovationinsightinterestmalemeetingsmicrobialmicrobiomemicrobiome researchmicroorganismnew therapeutic targetnovelnovel strategiespupreceptorreproductivereproductive axisreproductive functionresearch and developmentsecondary metabolitesexual dimorphismskillssubfertilitytherapeutic targettooltranslational impactvector
项目摘要
Recent studies suggest that the gut microbiome can influence fertility and the hypothalamic-pituitary-gonadal (HPG) axis through modifications of bile acids. The overall goal of this study is to determine whether the gut microbiome’s modulation of bile acids affects reproductive function and fertility. To have a better mechanistic understanding of how bacterial bile acid modifications affect reproductive health, there is a critical need for a tool that will introduce specific bacterial biotransformations into the gut microbiome and investigate their effects on the host HPG axis. An innovation of this proposal is a new strategy that allows us to quickly and effectively knock- in a beneficial function in a sustained manner, for perpetuity, by engineering the host’s native bacteria to induce a physiological change. The candidate will use this tool to address her central hypothesis, that bile acids are key modulators of the HPG axis and fertility. In the next three years, the candidate will pursue the proposal’s central hypothesis with three specific aims. The first aim will determine how bacterial bile acid biotransformations in the gut microbiome affect fertility in both male and female mice. By using engineered native bacteria to increase bile acid deconjugation, the candidate will determine the effect of altered bile acid composition on serum sex hormones and other markers host fertility. Overall, this aim will determine if there is sexual dimorphism in microbiome modulation of bile acids and host reproductive health. In the second aim, the candidate will evaluate the effect of bile signaling modulation and reduced serum androgen levels, shown in my preliminary results, on fecundity in a cohort of male mice. This will determine whether bile acid biotransformations elicit a strong enough effect on the reproductive axis to reduce fecundity in males. The third aim will determine whether the nuclear bile acid receptor, farnesoid X receptor (FXR), is necessary for the effect of bacterial bile acid biotransformations on testosterone levels. Ultimately, this aim will determine whether this receptor is a novel therapeutic target to manipulate fertility and fecundity. The expected outcome of these studies is further clarity about the relationship between bile acid signaling and reproductive health. The positive translational impact includes the determination of whether the gut microbiome can be used to better understand, and potentially treat, male and female subfertility. The candidate is an exceptional scientist whose goal is to become an independent scientist investigating the relationship between the gut microbiome and host reproductive health. Her training goals include developing expertise in reproductive physiology, designing microbiome experiments, developing expertise in animal models of disease, learning the skills necessary to become an independent researcher, and building her professional network. To accomplish these training goals, the candidate has outlined a plan with hands-on bench research, coursework, seminars, national meetings, and other career development opportunities under the guidance of mentorship committee led by Drs. Amir Zarrinpar and Pamela Mellon.
最近的研究表明,肠道微生物组可以通过胆汁酸的修饰影响生育能力和下丘脑-垂体-性腺 (HPG) 轴。本研究的总体目标是确定肠道微生物组对胆汁酸的调节是否影响生殖功能和生育能力。为了更好地了解细菌胆汁酸修饰如何影响生殖健康,迫切需要一种工具将特定的细菌生物转化引入肠道微生物组并研究其对宿主的影响HPG 轴的一项创新是一种新策略,它允许我们通过改造宿主的天然细菌来诱导生理变化,以持续的方式有效地敲入有益的功能。为了解决她的中心假设,即胆汁酸是 HPG 轴和生育力的关键调节剂,在接下来的三年中,候选人将通过三个具体目标来追求该提案的中心假设,第一个目标将确定细菌胆汁酸如何在体内进行生物转化。肠道微生物组影响雄性和雌性小鼠的生育力。通过使用工程化的天然细菌来增加胆汁酸的去除,候选者将确定胆汁酸成分对血清性激素和其他标志物宿主生育力的影响。胆汁酸微生物组调节和宿主生殖健康中的性别二态性在第二个目标中,候选人将评估胆汁信号调节和血清雄激素水平降低对一组生殖力的影响,如我的初步结果所示。这将确定胆汁酸生物转化是否对生殖轴产生足够强的影响,从而降低雄性小鼠的生育力。第三个目标将确定核胆汁酸受体法尼酯 X 受体 (FXR) 是否是其作用所必需的。最终,这一目标将确定该受体是否是控制生育力和生育力的新治疗靶点。这些研究的预期结果是进一步阐明胆汁酸信号传导与生殖健康之间的关系。积极的转化影响包括确定肠道微生物组是否可以用于更好地理解并潜在地治疗男性和女性生育力低下。该候选人是一位杰出的科学家,其目标是成为一名独立科学家,研究肠道微生物组与宿主之间的关系。她的培训目标包括发展生殖生理学方面的专业知识、设计微生物组实验、发展疾病动物模型方面的专业知识、学习成为独立研究人员所需的技能以及建立她的专业网络。亲手制定计划在 Amir Zarrinpar 和 Pamela Mellon 博士领导的指导委员会的指导下,我们提供了基础研究、课程作业、研讨会、全国会议和其他职业发展机会。
项目成果
期刊论文数量(0)
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Erica Maissy其他文献
Erica Maissy的其他文献
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{{ truncateString('Erica Maissy', 18)}}的其他基金
The Impact of Gut Bile Acid Deconjugation on Host Fertility
肠道胆汁酸解离对宿主生育力的影响
- 批准号:
10316112 - 财政年份:2022
- 资助金额:
$ 4.15万 - 项目类别:
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