Intersections between the maternal microbiome, placental immunity, vasculature and fetal growth

项目摘要 世界卫生组织将胎儿宫内生长受限（IUGR）确定为妊娠的主要危险因素。 不良围产期结果和长期健康后果。据估计， 在发展中国家和社会经济群体中的患病率甚至更高 他们的医疗条件有限。IUGR通常与母亲营养不良和胎盘 包括免疫功能障碍和血管生长受损，但环境因素如何 对这些过程的调控还没有完全了解。肠道微生物组介导环境 对宿主免疫功能和血管生成的贡献，微生物群组成受到 饮食摄入这保证了微生物组作为胎盘稳态的关键调节剂的研究， 开启了基于微生物的治疗策略来治疗IUGR的可能性。事实上，这种新颖的方法 改善妊娠期孕产妇健康和治疗IUGR符合NICHD的使命，特别是 确保“.妇女不受生殖过程的有害影响，所有儿童都享有 让他们有机会充分发挥潜力，过上健康和富有成效的生活。” 我的初步数据支持了中心假设，即在怀孕期间母体微生物组的生态失调 妊娠损害胎盘血管生成免疫细胞和脉管系统，导致下游异常， 胎儿发育此外，我的数据支持微生物组调节循环的假设， 具有已知免疫调节和血管生成潜力的代谢物，可以在整个过程中全身发挥作用， 主持人我的理论是，破坏母体微生物组，无论是通过细菌耗竭还是 通过母体营养，改变循环生化物质的生物利用度，这些生化物质对母体和胎儿至关重要。 怀孕期间的健康我打算用以下目标来检验我的中心假设：目标1：调查 母体微生物组对胎盘免疫稳态的影响;目的2：检查母体微生物组如何影响胎盘免疫稳态。 微生物组调节胎盘血管发育;目的3：确定 母体微生物组对胎儿生长的影响完成后，我将提供新的见解如何产妇 微生物组通过特定的分子相互作用调节胎盘免疫和血管稳态。 这种机械方法是重要的，因为它揭示了微生物组作为一种生物学行为的因果作用。 IUGR的调节剂，并打开了基于微生物组的治疗靶点的潜力，以显着改善 全球范围内的孕产妇和胎儿健康 拟议中的研究对我的博士前培训至关重要，因为我将发展和完善我的 技术技能，实验设计和分析，以及来自多个领域的科学文献的批判性评论。

PROJECT SUMMARY The World Health Organization identifies intrauterine growth restriction (IUGR) as a primary risk factor for adverse perinatal outcomes and long-term health consequences. It afflicts an estimated 100,000 children born each year in the United States, with even higher prevalence in developing countries and socioeconomic groups with limited access to healthcare. IUGR is commonly associated with poor maternal nutrition and placental insufficiencies, including immune dysfunction and impaired vascular growth, but how environmental factors regulate these processes is not completely understood. The gut microbiome mediates environmental contributions to host immune function and angiogenesis, and microbiota composition is markedly influenced by dietary intake. This warrants investigation of the microbiome as a critical regulator of placental homeostasis, opening the possibility for microbiota-based therapeutic strategies to treat IUGR. Indeed, this novel approach to improve maternal health during gestation and treat IUGR aligns with the NICHD mission, specifically to ensure “…that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives.” My preliminary data supports the central hypothesis that dysbiosis of the maternal microbiome during pregnancy impairs placental angiogenic immune cells and vasculature, leading to downstream abnormalities in fetal development. Further, my data supports the presumption that the microbiome regulates circulating metabolites that have known immunoregulatory and angiogenic potential that can act systemically throughout the host. My rationale is that disrupting the maternal microbiome, whether through bacterial depletion or through maternal nutrition, alters bioavailability of circulating biochemicals that are critical for maternal and fetal health during pregnancy. I propose to test my central hypothesis with the following aims: Aim 1: Investigate effects of the maternal microbiome on placental immune homeostasis; Aim 2: Examine how the maternal microbiome regulates placental vascular development; Aim 3: Determine mechanistic influences of the maternal microbiome on fetal growth. Upon completion, I will provide novel insights into how the maternal microbiome regulates placental immune and vascular homeostasis through specific molecular interactions. This mechanistic approach is significant because it sheds light on a causal role of the microbiome as a regulator of IUGR, and opens the potential for microbiome-based therapeutic targets to markedly improve maternal and fetal health on a global scale. The proposed research is of critical importance for my predoctoral training, as I will develop and refine my technical skills, experimental design and analysis, and critical review of scientific literature from multiple fields.