Diversity Supplement to Microvascular mechanisms of growth restriction after environmental toxicant exposure (R01ES031285)

环境毒物暴露后生长受限的微血管机制的多样性补充（R01ES031285）

• 批准号: 10849145
• 负责人: Phoebe Stapleton
• 金额: $ 1.76万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10849145
• 关键词: Acute; Aerosols; Animals; Arachidonic Acids; Attenuated; Award; Blood Vessels; Blood flow; Child; Chronic; Circulation; Development; Dietary Intervention; Endothelium; Environmental Exposure; Evaluation; Exposure to; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal health; Fetus; Growth; Health; Impairment; Inhalation; Intervention; Joints; Laboratories; Maternal Exposure; Maternal-fetal medicine; Metabolism; Methodology; Microcirculation; Microvascular Dysfunction; Molecular; Mothers; National Institute of Environmental Health Sciences; Nitric Oxide; Nutrient; Particulate; Particulate Matter; Pathogenesis; Patients; Perfusion; Placenta; Pregnancy; Pregnant Women; Premature Birth; Regulation; Research; Resources; Risk; Risk Factors; Rodent Model; Role; Signal Transduction; Spontaneous abortion; Students; Testing; Therapeutic; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Toxicology; Universities; Uterus; Vascular Endothelium; Vascularization; Vasodilation; Work; design; dietary; epidemiology study; fetal; fetal blood; fetal loss; fine particles; folic acid supplementation; hemodynamics; improved; innovation; insight; nanomaterials; nanosized; novel; novel strategies; nutritional supplementation; parent grant; programs; targeted treatment; titanium dioxide

PARENT GRANT ABSTRACT The uterine circulation and placenta are specifically designed to regulate the flow of blood and transport of essential nutrients to the fetus. Disruption of maternal hemodynamic regulation during pregnancy can adversely impact fetal health, resulting in miscarriage and intrauterine growth restriction (IUGR). Current treatment options for IUGR patients are extremely limited, focusing primarily on early delivery; thus, putting the mother and child at risk for complications associated with preterm birth. Epidemiological studies indicate that pregnant women exposed to fine particulate matter (PM) have a heightened risk of fetal loss and development of IUGR. We have reproduced this phenomenon in laboratory rodent models, wherein animals exposed to nanosized titanium dioxide (nano-TiO2) aerosols develop IUGR and suffer a greater number of ‘miscarriages’ (fetal reabsorptions). We have demonstrated that acute and chronic exposures significantly impair uterine vascular endothelium dependent dilation, severely limiting maternal-to-fetal blood flow and impacting fetal growth. Unfortunately, current research strategies have yet to elucidate the vascular mechanisms associated with the development of IUGR after maternal particulate exposure. Based on previous findings, we hypothesize that maternal inhalation of nano-TiO2 aerosols during pregnancy promotes the development of IUGR by disrupting endothelium- dependent signaling cascades, resulting in a net reduction in uterine vasodilation and blood flow. We further postulate that IUGR will be mitigated by improved vascular signaling and function after nutritional supplementation with folic acid. Using novel approaches and methodologies, these studies will: (1) evaluate uterine nitric oxide-driven vasodilation, (2) determine whether alterations in arachidonic acid metabolism impair uterine vascular reactivity and impact placental perfusion, and (3) assess the therapeutic benefit of dietary folic acid supplementation to improve utero-placental blood flow and attenuate the development of IUGR after maternal exposure to nano-TiO2 aerosols. These studies are conceptually innovative as we will utilize our unique resources to identify mechanistic targets within the utero-placental microcirculation and test directed nutritional interventions for IUGR. This work is technically innovative as we will use novel methodologies developed for the evaluation of environmental toxicity in maternal-fetal medicine. Overall, the successful completion of these studies will: (1) create the conceptual framework to identify environmental exposure as a risk factor for the development of IUGR; (2) reveal new mechanistic insight into the vascular pathogenesis resulting from nanomaterial exposure; (3) provide a molecular basis to identify how nanomaterial exposure manifests as vascular disruptions; and (4) identify mechanistic targets for therapeutic strategies to ameliorate microvascular dysfunction and improve utero-placental blood flow. These interventional strategies are not only limited to PM, but are widely applicable to understanding the role of a spectrum of environmental toxicants in the pathophysiological development of IUGR.

专利授权摘要 子宫循环和胎盘是专门设计来调节血液的流动和运输， 胎儿的必需营养素妊娠期间母体血流动力学调节的中断可 影响胎儿健康，导致流产和宫内生长受限（IUGR）。当前治疗选择 对于IUGR患者来说是非常有限的，主要集中在早期分娩;因此， 有早产并发症的风险。流行病学研究表明， 暴露于细颗粒物（PM）的孕妇有更高的胎儿丢失和IUGR发展的风险。我们有 在实验室啮齿动物模型中重现了这种现象，其中动物暴露于纳米级钛 二氧化物（纳米二氧化钛）气溶胶发展IUGR和遭受更多的“流产”（胎儿排斥）。 我们已经证明，急性和慢性暴露显着损害子宫血管内皮细胞 依赖性扩张，严重限制母胎血流并影响胎儿生长。很不幸的是， 目前的研究策略还没有阐明与发展相关的血管机制， 母体颗粒物暴露后的IUGR。基于先前的发现，我们假设母体吸入 纳米二氧化钛气溶胶在怀孕期间促进IUGR的发展，通过破坏内皮细胞- 依赖性信号级联，导致子宫血管舒张和血流的净减少。我们 进一步假设IUGR将通过营养后改善血管信号和功能来减轻， 补充叶酸。使用新的方法和手段，这些研究将：（1）评估 子宫一氧化氮驱动的血管舒张，（2）确定花生四烯酸代谢的改变是否损害 子宫血管反应性和影响胎盘灌注，以及（3）评估膳食叶酸的治疗益处 补充酸以改善子宫胎盘血流并减弱IUGR的发展， 母体暴露于纳米二氧化钛气溶胶。这些研究在概念上是创新的，因为我们将利用我们独特的 资源，以确定子宫胎盘微循环内的机制目标和测试定向营养 干预IUGR。这项工作在技术上是创新的，因为我们将使用为 母胎医学环境毒性评价。总的来说，成功完成这些 研究将：（1）建立概念框架，以确定环境暴露是 IUGR的发展;（2）揭示了血管发病机制的新见解， （3）提供分子基础，以确定纳米材料暴露如何表现为 血管破坏;和（4）确定治疗策略的机制靶点，以改善微血管 改善子宫-胎盘血流。这些干预策略不仅限于PM， 但广泛适用于理解一系列环境毒物在 IUGR的病理生理发展。