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 proposal 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Transition Award (R00)
Project #
5R00AA019446-04
Application #
8327215
Study Section
Special Emphasis Panel (NSS)
Program Officer
Dunty, Jr, William
Project Start
2010-04-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$249,000
Indirect Cost
$86,255
Name
University of Texas Medical Br Galveston
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C et al. (2016) Alcohol-Induced Developmental Origins of Adult-Onset Diseases. Alcohol Clin Exp Res 40:1403-14
Ampey, Bryan C; Morschauser, Timothy J; Ramadoss, Jayanth et al. (2016) Domain-Specific Partitioning of Uterine Artery Endothelial Connexin43 and Caveolin-1. Hypertension 68:982-8
Mayra, Pastore R; Rosalina, Villalón L; López, Gladys et al. (2014) [Regulation of uterine blood flow. II. Functions of estrogen and estrogen receptor α/β in genomic and non-genomic actions of the uterine endothelium]. Rev Chil Obstet Ginecol 79:218-228
Subramanian, Kaviarasan; Naik, Vishal D; Sathishkumar, Kunju et al. (2014) Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation. Reprod Toxicol 43:94-101
Ramadoss, Jayanth; Pastore, Mayra B; Magness, Ronald R (2013) Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase. Clin Exp Pharmacol Physiol 40:753-64
Chinnathambi, Vijayakumar; Balakrishnan, Meena; Ramadoss, Jayanth et al. (2013) Testosterone alters maternal vascular adaptations: role of the endothelial NO system. Hypertension 61:647-54
Sawant, Onkar B; Ramadoss, Jayanth; Hogan, Harry A et al. (2013) The role of acidemia in maternal binge alcohol-induced alterations in fetal bone functional properties. Alcohol Clin Exp Res 37:1476-82
Ramadoss, Jayanth; Liao, Wu-xiang; Morschauser, Timothy J et al. (2012) Endothelial caveolar hub regulation of adenosine triphosphate-induced endothelial nitric oxide synthase subcellular partitioning and domain-specific phosphorylation. Hypertension 59:1052-9
Ramadoss, Jayanth; Magness, Ronald R (2012) Alcohol-induced alterations in maternal uterine endothelial proteome: a quantitative iTRAQ mass spectrometric approach. Reprod Toxicol 34:538-44
Pastore, Mayra B; Jobe, Sheikh O; Ramadoss, Jayanth et al. (2012) Estrogen receptor-α and estrogen receptor-β in the uterine vascular endothelium during pregnancy: functional implications for regulating uterine blood flow. Semin Reprod Med 30:46-61

Showing the most recent 10 out of 11 publications