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）：至少在某种程度上，由于对酒精损害发育中胎儿的机制的机制的有限理解，至少在某种程度上阻碍了成功预防或改善酒精的致化作用的努力。在这笔K99/R00赠款中，我们将探讨胎儿酒精谱系（FASD）的母体子宫起源，并为未来蛋白质组学生物标志物（S）/独特的母体酒精消耗型制定制定策略。整个子宫循环的协调生长和重塑和胎盘的创造是正常胎儿发育的必要条件。这些复杂的过程由内皮衍生的一氧化氮（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慢性暴饮暴食的直接影响：1）妊娠期间子宫动脉内皮中的NO和ENOS相关的信号级联反应； 2）Caveolae是eNOS的天然家园，并利用这些知识来开发高吞吐量的蛋白质组学生物标志物（S）/独特的招牌概况，以供孕妇饮酒，这是NIAAA战略计划的2009 - 2014年。独特的途径调节孕妇子宫中的NO和eNOS，这些途径在与妊娠相关的母体子宫血管适应中起着独特的作用。在特定的目标＃1中，我们将直接比较孕妇子宫动脉内皮细胞中狂饮介导的适应性反应和特定的信号通路，并在剪切应力下通过分级的脉冲脉冲在体内流动条件下进行分级。从这些研究中得出的数据将为理解剪切应力与酒精之间的相互作用提供第一个机械框架，以调节怀孕子宫内皮的产生。暴饮暴食改变了eNOS与Cav-1之间的化学计量关系，随着酒精的每一批酒精，[Ca+2] I中有显着的上升，进而将eNOS驱逐出Caveolae，这是其“自然家园”，它是一个主要的稳定环境。在特定的目标＃2中，我们将研究[CA+2] I中酒精诱导的反复细胞内增加及其对Caveolae反复耗尽eNOS的影响，无生产。在特定的目标＃3中，我们将利用高吞吐量蛋白质组学来识别依赖于酒精侮辱水平的生物标志物/独特的Caveolar特征蛋白谱。这些发现将使我们处于理解酒精损害的多种力学原因的绝佳位置，尤其是从母亲和子宫的角度来看，并正确设计并提出了全面的预防策略。 公共卫生相关性：每年，至少有40,000名婴儿在美国出生，每个人估计成本为140万美元，总成本至少为60亿美元。至少在某种程度上，由于对酒精损害发育中的胎儿的机制的理解，至少在某种程度上阻碍了成功预防或改善酒精的致化作用的努力。在这项K99/R00赠款中，我们将探索胎儿酒精谱系（FASD）的母体子宫起源，并制定了开发策略，以实现高吞吐量蛋白质组学生物标志物（S）/独特的母体酒精消费率。

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