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.

父授予摘要 子宫循环和斑点是专门设计的，以调节血液的流动和运输 胎儿的必需营养素。怀孕期间孕产妇血流动力学调节的破坏会对 影响胎儿健康，从而导致流产和次氨酸内生长限制（IUGR）。当前的治疗选择 对于IUGR患者，患者极有限，主要集中在早期分娩上；因此，把母子和孩子放在 与早产相关的并发症的风险。流行病学研究表明孕妇 暴露于特定问题（PM）的胎儿流失和IUGR发育的风险增加。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钛中 二氧化二氧化碳（纳米-TIO2）气溶胶会发展出IUGR，并遭受更多的“流产”（胎儿回收）。 我们已经证明，急性和慢性暴露会严重损害子宫血管内皮 依赖的词典，严重限制了母子对狂热的血流和影响胎儿的生长。很遗憾， 当前的研究策略尚未阐明与发展相关的血管机制 母体颗粒物暴露后的IUGR。根据先前的发现，我们假设孕产妇吸入 怀孕期间的纳米-TIO2气溶胶可通过破坏森植物来促进IUGR的发展 依赖的信号传导级联反应，导致子宫血管舒张和血流的净减少。我们 进一步假设，营养后的血管信号传导和功能改善了IUGR 补充叶酸。使用新颖的方法和方法，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斑点灌注，（3）评估饮食叶的治疗益处 补充酸以改善子宫牙性血流并衰减IUGR的发育 孕妇接触纳米-TIO2气溶胶。这些研究在概念上是创新的，因为我们将利用我们的独特 资源以识别子宫位微循环中的机械目标并测试有向营养 IUGR的干预措施。这项工作在技术上具有创新性，因为我们将使用为 评估产妇医学中的环境毒性。总体而言，这些成功完成 研究将：（1）创建概念框架，以识别环境暴露为危险因素 IUGR的发展； （2）揭示了对由 纳米材料暴露； （3）提供了分子基础，以确定纳米材料暴露如何表现为 血管干扰； （4）确定修复微血管的治疗策略的机理目标 功能障碍并改善子宫斑血流。这些介入策略不仅限于PM 但广泛适用于理解一系列环境有毒物质在 IUGR的病理生理发展。