Maternal Uterine Vascular Origins of Fetal Alcohol Spectrum Disorders

胎儿酒精谱系疾病的母体子宫血管起源

• 批准号: 8040970
• 负责人: Jayanth Ramadoss
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040970
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; Address; Affect; Agonist; Alcohol consumption; Alcohol-Induced Disorders; Alcoholism; Alcohols; Arteries; Award; Behavior Therapy; Biological; Biological Markers; Biological Models; Birds; Blood; Blood Circulation; Blood Vessels; Blood flow; Calcium; Cardiovascular system; Caveolae; Cell Culture Techniques; Centrifugation; Chronic; Confocal Microscopy; Consult; Data; Development; Early identification; Endothelial Cells; Endothelium; Environment; Enzymes; Erythrocytes; Fetal Alcohol Spectrum Disorder; Fetal Development; Fetus; Future; Gene Expression; Gene Proteins; Goals; Grant; Growth; Home environment; Image; Immunoblotting; In Vitro; Individual; Knowledge; Label; Lead; Lipids; MAPK3 gene; Mass Spectrum Analysis; Measurement; Mediating; Membrane Microdomains; Mentorship; Modality; Mothers; National Institute on Alcohol Abuse and Alcoholism; Nitric Oxide; Nutritional; Pathogenesis; Pathway interactions; Peer Review; Phase; Phosphorylation; Phosphorylation Site; Physiological; Placenta; Play; Positioning Attribute; Post-Translational Protein Processing; Pregnancy; Pregnant Uterus; Pregnant Women; Prevention; Process; Production; Protein Array; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Publishing; Pulsatile Flow; Reporting; Research; Research Personnel; Role; Scaffolding Protein; Set protein; Signal Pathway; Signal Transduction; Site; Societies; Specificity; Strategic Planning; Techniques; Testing; Third Pregnancy Trimester; Time; Training; Translating; Treatment Efficacy; Uterus; Vascular remodeling; Western Blotting; Woman; abstracting; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol measurement; base; caveolin 1; cell type; cost; design; drinking; enzyme activity; fetal; high throughput technology; human NOS3 protein; in vivo; novel; pregnant; prevent; protein expression; protein profiling; public health relevance; response; shear stress

DESCRIPTION (provided by applicant): Efforts to successfully prevent or ameliorate the teratogenic effects of alcohol have been impeded, at least in part, by a limited understanding of the mechanisms by which alcohol damages the developing fetus. In this K99/R00 grant, we will explore the maternal uterine origins of Fetal Alcohol Spectrum Disorders (FASD) and devise a strategy for development of a future proteomic biomarker(s)/unique signature profile for maternal alcohol consumption. Coordinated growth and remodeling of the entire uterine circulation and creation of a placenta are requisites for normal fetal development. These intricate processes are controlled by endothelial-derived nitric oxide (NO) and enzyme activity of endothelial nitric oxide synthase (eNOS). The overall goal of this application is to investigate the direct effects of chronic binge alcohol on: 1) NO and eNOS-related signaling cascades in the uterine artery endothelium during pregnancy; and 2) the caveolae, the natural home for eNOS, and to utilize this knowledge to develop a high throughput proteomic biomarker(s)/unique signature profile for maternal alcohol consumption, a stated goal of NIAAA strategic plan for years 2009-2014. Unique pathways regulate NO and eNOS in the pregnant uterus and these play a distinct role in pregnancy-associated maternal uterine vascular adaptations. In specific aim#1, we will directly compare binge alcohol mediated adaptive responses and specific signaling pathways in the pregnant uterine artery endothelial cells under shear stress via graded pulsatile in vivo-like flow conditions. Data derived from these studies will provide the first mechanistic framework for understanding the interactions between shear stress and alcohol to regulate NO production in pregnant uterine endothelium. Binge alcohol alters the stoichiometric relationship between eNOS and cav-1 and with every bout of alcohol, there are significant rises in [Ca+2]i and in turn eNOS is driven away from the caveolae, its "natural home" which acts as a major stabilizing environment. In specific aim #2, we will investigate alcohol-induced repeated intracellular increases in [Ca+2]i and its effects on repeated depletion of eNOS from caveolae and NO production. In specific aim #3, we will utilize high throughput proteomics to identify a biomarker(s)/unique caveolar signature protein profile that is dependent on the level of alcohol insult. These findings will place us in an excellent position to understand the multimechanistic causes of alcohol damage, especially from the perspective of the mother and the uterus, and to correctly design and propose a comprehensive preventative strategy. PUBLIC HEALTH RELEVANCE: Each year, at least 40,000 babies are born with FASD in the U.S. at an estimated cost of $1.4 million per individual and total cost of at least $6 billion. Efforts to successfully prevent or ameliorate the teratogenic effects of alcohol have been impeded, at least in part, by a limited understanding of the mechanisms by which alcohol damages the developing fetus. In this K99/R00 grant, we will explore the maternal uterine origins of Fetal Alcohol Spectrum Disorders (FASD) and devise a strategy for development a high throughput proteomic biomarker(s)/unique signature profile for maternal alcohol consumption.

描述（由申请人提供）：由于对酒精损害发育中胎儿的机制了解有限，至少部分地阻碍了成功预防或改善酒精致畸作用的努力。在这笔 K99/R00 拨款中，我们将探索胎儿酒精谱系障碍 (FASD) 的母体子宫起源，并制定一项开发未来蛋白质组生物标志物/母体饮酒独特特征谱的策略。整个子宫循环的协调生长和重塑以及胎盘的形成是胎儿正常发育的必要条件。这些复杂的过程由内皮源性一氧化氮 (NO) 和内皮一氧化氮合酶 (eNOS) 的酶活性控制。该应用的总体目标是研究长期酗酒对以下方面的直接影响： 1) 妊娠期间子宫动脉内皮细胞中 NO 和 eNOS 相关信号级联； 2) 小窝（eNOS 的天然家园），并利用这些知识开发高通量蛋白质组生物标志物/孕产妇饮酒的独特特征谱，这是 NIAAA 2009-2014 年战略计划的既定目标。独特的途径调节妊娠子宫中的 NO 和 eNOS，这些途径在妊娠相关的母体子宫血管适应中发挥着独特的作用。在具体目标#1中，我们将通过分级脉动体内样流动条件直接比较剪切应力下怀孕子宫动脉内皮细胞中酗酒介导的适应性反应和特定信号通路。从这些研究中获得的数据将为理解剪切应力和酒精之间的相互作用来调节妊娠子宫内皮细胞一氧化氮的产生提供第一个机制框架。暴饮暴食会改变 eNOS 和 cav-1 之间的化学计量关系，每次饮酒后，[Ca+2]i 都会显着升高，进而 eNOS 会远离小凹，它的“天然家园”充当着主要稳定环境。在具体目标 2 中，我们将研究酒精诱导的细胞内 [Ca+2]i 反复增加及其对小凹中 eNOS 反复消耗和 NO 产生的影响。在具体目标#3中，我们将利用高通量蛋白质组学来识别依赖于酒精损伤水平的生物标志物/独特的小凹特征蛋白谱。这些发现将使我们能够很好地理解酒精损伤的多机制原因，特别是从母亲和子宫的角度，并正确设计和提出全面的预防策略。 公共卫生相关性：在美国，每年至少有 40,000 名婴儿出生时患有 FASD，估计每人花费 140 万美元，总花费至少 60 亿美元。由于对酒精损害发育中胎儿的机制了解有限，成功预防或改善酒精致畸作用的努力至少部分受到阻碍。在这笔 K99/R00 拨款中，我们将探索胎儿酒精谱系障碍 (FASD) 的母体子宫起源，并制定一项策略来开发母体饮酒的高通量蛋白质组生物标志物/独特的特征谱。

项目成果

Chronic binge alcohol exposure during pregnancy impairs rat maternal uterine vascular function.

• DOI: 10.1111/acer.12431
• 发表时间: 2014-07
• 期刊: Alcoholism, clinical and experimental research
• 作者: Subramanian K;Naik VD;Sathishkumar K;Yallampalli C;Saade GR;Hankins GD;Ramadoss J
• 通讯作者: Ramadoss J

Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation.

• DOI: 10.1016/j.reprotox.2013.11.006
• 发表时间: 2014-01
• 期刊: Reproductive toxicology (Elmsford, N.Y.)
• 作者: Subramanian K;Naik VD;Sathishkumar K;Sawant OB;Washburn SE;Wu G;Yallampalli C;Saade GR;Hankins GD;Ramadoss J
• 通讯作者: Ramadoss J