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

项目总结 世界卫生组织将宫内生长受限(IUGR)确定为 不良的围产期结局和长期的健康后果。据估计，有10万名出生的儿童患有此病 每年在美国，发展中国家和社会经济群体的流行率甚至更高 获得医疗保健的机会有限。IUGR通常与母亲营养不良和胎盘有关 不足，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被理解。肠道微生物群调节环境 对宿主免疫功能和血管生成的贡献，以及微生物区系组成明显受 饮食摄入量。这需要研究微生物群作为胎盘动态平衡的关键调节因素， 为基于微生物群的治疗IUGR策略打开了可能性。事实上，这种新的方法 改善孕期孕产妇健康和治疗IUGR符合NICHD的使命，特别是 确保“…”妇女不会受到生殖过程的有害影响，所有的孩子都有 有机会充分发挥他们的潜力，过上健康和富有成效的生活。 我的初步数据支持这样一个中心假设，即母体微生物群在 妊娠损害胎盘血管生成免疫细胞和血管系统，导致胎盘下游异常 胎儿发育。此外，我的数据支持微生物群调节循环的假设 具有已知的免疫调节和血管生成潜力的代谢物，可在整个过程中发挥系统作用 主持人。我的理由是，无论是通过细菌枯竭还是通过 通过母体营养改变对母体和胎儿至关重要的循环生物化学物质的生物利用度 孕期健康。我建议用以下目标来检验我的中心假设：目标1：调查 母体微生物群对胎盘免疫动态平衡的影响；目标2：检查母体如何 微生物组调节胎盘血管发育；目标3：确定微生物组对胎盘血管发育的影响 母体微生物群对胎儿生长发育的影响。在完成后，我将提供关于母体如何 微生物组通过特定的分子相互作用调节胎盘免疫和血管动态平衡。 这种机械论方法很重要，因为它揭示了微生物群作为一种 IUGR的调节剂，并为基于微生物组的治疗靶点显著改进打开了可能性 全球范围内的孕产妇和胎儿健康。 拟议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，以及对来自多个领域的科学文献的批判性审查。

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.