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.
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.
|Naik, Vishal D; Davis-Anderson, Katie; Subramanian, Kaviarasan et al. (2018) Mechanisms Underlying Chronic Binge Alcohol Exposure-Induced Uterine Artery Dysfunction in Pregnant Rat. Alcohol Clin Exp Res 42:682-690|
|Lunde-Young, Raine; Davis-Anderson, Katie; Naik, Vishal et al. (2018) Regional dysregulation of taurine and related amino acids in the fetal rat brain following gestational alcohol exposure. Alcohol 66:27-33|
|Davis-Anderson, Katie L; Wesseling, Hendrik; Siebert, Lara M et al. (2018) Fetal regional brain protein signature in FASD rat model. Reprod Toxicol 76:84-92|
|Davis-Anderson, Katie L; Berger, Sebastian; Lunde-Young, Emilie R et al. (2017) Placental Proteomics Reveal Insights into Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res 41:1551-1558|
|Naik, Vishal D; Lunde-Young, Emilie R; Davis-Anderson, Katie L et al. (2016) Chronic binge alcohol consumption during pregnancy alters rat maternal uterine artery pressure response. Alcohol 56:59-64|
|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|
|Subramanian, Kaviarasan; Naik, Vishal D; Sathishkumar, Kunju et al. (2014) Chronic binge alcohol exposure during pregnancy impairs rat maternal uterine vascular function. Alcohol Clin Exp Res 38:1832-8|
|Sawant, Onkar B; Ramadoss, Jayanth; Hankins, Gary D et al. (2014) Effects of L-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol. Amino Acids 46:1981-96|
|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|
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