Maternal alcohol consumption during early pregnancy is difficult to prevent due to the prevalence of both unplanned pregnancies and binge patterns of alcohol consumption in the US. Exposure is common during the 1st trimester, when neural stem cells (NSCs) begin producing neurons, increasing the risk for neurodevelopmental disability. There is a critical, un-met need for biomedical interventions to mitigate effects of alcohol exposure. A lack of such interventions means that we can do little to help women who subsequently seek prenatal care for fetal alcohol exposure. Our long-term goal is to find ways to mitigate brain damage due to teratogens like ethanol. Our approach to reversing ethanol's effects focuses on intervening prenatally to manipulate the growth potential of residual fetal NSCs. This approach is based on our key findings that ethanol does not kill NSCs, but promotes premature maturation. A class of small regulatory RNAs, miRNAs, mediates many of these ethanol effects. Ethanol deregulates miRNA (miR153, miR335) control of differentiation-promoting transcription factors (ndTFs) like Nfia and Nfib and NeuroD1, resulting in premature ndTF expression in NSCs. Moreover, nicotinic acetylcholine receptor (nAChR) agonists can prevent and even reverse effects of ethanol on miRNAs and their target ndTFs. Collectively, these data support two hypotheses: (1) ethanol depletes NSCs by interfering with miRNA-ndTF networks that prevent premature NSC maturation, and (2) both miRNAs and nAChR agonists prevent and perhaps even reverse effects of fetal ethanol exposure.
Aim 1 will identify key ndTFs that facilitate ethanol effects on NSC self-renewal and maturation while Aim 2 will identify key miRNAs that block ethanol effects.
Aim 3 will identify pharmacological interventions that control miRNA-ndTF networks and prevent ethanol- mediated loss of NSCs. We will assess direct nAChR effects (i.e., varenicline exposure), as well as ndTF- and miRNA-mediated effects of nAChR activation, on NSC renewal and maturation. In these aims, we will manipulate ndTFs and miRNAs with innovative viral-mediated strategies, and a novel murine inducible reporter model to track affected NSCs and their daughter progeny. This proposal is significant in that it is expected to lay the theoretical and experimental framework for a new approach to address the un-met need for reparative fetal therapy to prevent FASD. It is innovative because it advances a novel conceptual model that links a cellular target (miRNA-ndTF networks) to a therapeutic approach (varenicline and nAChR pharmacology), to reprogram neurogenesis in the aftermath of alcohol exposure. As an outcome of these studies we expect to identify core molecular and pharmacological approaches to repair fetal damage following exposure to a potent and common teratogen, alcohol.

Public Health Relevance

Fetal alcohol spectrum disorders (FASD) is the leading non-genetic cause of neurodevelopmental disability, and a significant public health and socio-economic burden. FASD is difficult to prevent because of the continued prevalence of both unplanned pregnancies and binge patterns of ethanol consumption in the US. Therefore, in addition to education programs aimed at decreasing drinking during pregnancy, there is also a significant and un-met public health need to find ways to mitigate fetal damage due to early maternal alcohol consumption. The current proposal focuses on the identifying molecular biological principles (miRNA- transcription factor networks) and pharmacological approaches (nicotinic acetylcholinergic) to reprogram neural stem cells to overcome deficits in brain growth due to early (1st trimester-equivalent) fetal alcohol exposure. This proposal is responsive to PA-12-233, 'Stem Cells and Alcohol-induced Tissue Injuries', with specific reference to the mechanisms of 'intrinsic and extrinsic signals and signaling pathways regulating stem cell renewal, proliferation, differentiation, and niche'.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA024659-03
Application #
9433587
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Chin, Hemin R
Project Start
2016-03-10
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Burrowes, Sasha G; Salem, Nihal A; Tseng, Alexander M et al. (2017) The BAF (BRG1/BRM-Associated Factor) chromatin-remodeling complex exhibits ethanol sensitivity in fetal neural progenitor cells and regulates transcription at the miR-9-2 encoding gene locus. Alcohol 60:149-158
Bake, Shameena; Gardner, Rachel; Tingling, Joseph D et al. (2017) Fetal Alcohol Exposure Alters Blood Flow and Neurological Responses to Transient Cerebral Ischemia in Adult Mice. Alcohol Clin Exp Res 41:117-127
Balaraman, Sridevi; Idrus, Nirelia M; Miranda, Rajesh C et al. (2017) Postnatal choline supplementation selectively attenuates hippocampal microRNA alterations associated with developmental alcohol exposure. Alcohol 60:159-167
Ma, Tengfei; Barbee, Britton; Wang, Xuehua et al. (2017) Alcohol induces input-specific aberrant synaptic plasticity in the rat dorsomedial striatum. Neuropharmacology 123:46-54
Mahnke, Amanda H; Miranda, Rajesh C; Homanics, Gregg E (2017) Epigenetic mediators and consequences of excessive alcohol consumption. Alcohol 60:1-6