Program Director/Principal Investigator (Last, First, Middle): Gardiner, Amy S. PROJECT SUMMARY Fetal alcohol spectrum disorder (FASD) describes a spectrum of individuals who experience some disability as a result of prenatal alcohol exposure (PAE). It includes fetal alcohol syndrome (FAS), partial FAS, and alcohol- related neurodevelopmental disorder. In the United States, the incidence of FAS is estimated to be 2-7/1,000 live births, and for FASD, the incidence may be as high as 20-50/1,000 children. FASD patients have a wide range of motor, behavioral, and neurocognitive deficits as a result of insult to the developing brain. Considering the intimate relationship and the extensive molecular crosstalk during neuronal development and vascular development, it is likely that abnormal development of the brain vasculature may contribute to PAE-associated deficits. We found that a microRNA, miR-150-5p, which binds and downregulates Vegfa in models of vascular injury, was significantly increased in the cortices of fetuses prenatally exposed to alcohol. In addition, we identified the endothelial-specific transcription factor Vezf1, which was significantly reduced in the same tissues, as a novel direct target of miR-150-5p. We plan to identify additional angiogenic targets of miR-150-5p and investigate the role of miR-150-5p in regulating angiogenesis in the developing brain both in vitro and in vivo during PAE. This study will shed light on novel mechanisms that contribute to the teratogenic effects associated with PAE and may provide insight for reversing some of those effects.
Gardiner, Amy S. PROJECT NARRATIVE Although preventable, fetal alcohol spectrum disorders affect an alarmingly high number of children in the United States, up to 20-50/1,000 children. There are no current treatments that can reverse the damage to the developing fetus as a result of prenatal alcohol exposure (PAE), and thus understanding the mechanisms by which PAE affects brain structure and function are critical. This study will uncover microRNA-mediated mechanisms that drive changes in the developing brain vasculature during PAE.
