Alcohol intake during pregnancy causes wide varieties of acute and long-lasting adverse effects on fetuses, resulting in fetal alcohol spectrum disorders (FASD) in offspring. Especially, the developing brain is sensitive to alcohol toxicity, and impairments in cognitive functions, such as learning and memory, can be seen in FASD patients. While many factors may be involved in alcohol toxicity in the developing brain, the retinoic acid (RA) signaling pathway is often implicated in the process of alcohol toxicity, because RA (the active form of vitamin A) that regulates transcription and translation via nuclear RA receptors plays an important role in the development of embryos and their CNS, and alcohol has been shown to disturb retinoid (compounds related to vitamin A) metabolism. While precise control of RA distribution within embryonic cell populations seems to be necessary, and the excess or depletion of RA in the CNS has been shown to disturb brain development, alcohol interferes with retinoid metabolism by several mechanisms, resulting in activation or inactivation of the RA signaling pathway. Therefore, the RA signaling pathway may serve as a target for developing therapeutic applications in alcohol toxicity in the developing brain. This translational research proposal aims to determine if administration of novel retinoid derivatives (RA receptor agonists and antagonists) synthesized in the laboratory of Dr. Bhaskar Das (PI, Icahn School of Medicine at Mount Sinai) alleviates prenatal or neonatal alcohol-induced acute neurodegeneration as well as long-lasting abnormalities in neurogenesis, neuroanatomy, and behavior, using mouse models of FASD in the laboratory of Dr. Mariko Saito (Co-PI, Nathan Kline Research Institute).
The specific aims of this project are:
Aim. 1: To synthesize additional novel retinoids from our lead molecules that are fully characterized for specificity and bioactivity (Dr. Das? s group; see Nature Chemical Biology 2013 PMID: 23584676, PLos One 2011 PMID:22125642 and PLos One 2010 PMID: 20368991). Then we will iterate the process to synthesize additional compounds, which are more resistant to protease cleavage, more potent, and more specific to receptors. In the specific Aim 2, we will determine if RA receptor agonists or antagonists prevent early alcohol-induced abnormalities in cell survival, neurogenesis, neuroanatomy and behaviors. Alcohol, with or without RA derivatives, will be injected into dams at gestational day 8 (GD8) (1st trimester model) or pups at postnatal day 7 (P7) (3rd trimester model), and we will assess whether RA derivatives attenuate alcohol-induced acute neurodegeneration and long-lasting abnormalities in neurogenesis, GABAergic cell densities, and behaviors (locomotor activity and contextual fear conditioning). Successful completion of this translational research program will help identify target retinoid derivatives to be developed for the treatment for FASD.
RESEARCH NARRATIVE Alcohol intake during pregnancy causes wide varieties of acute and long-lasting adverse effects on fetal development especially in the brain, which may lead to fetal alcohol spectrum disorders (FASDs) in offspring, and FASDs, which occur in approximately 2?5 in 100 births, are the leading cause of non-heritable mental disability in the United States. While many factors may be involved in pathogenesis of FASD, the effects of alcohol on the retinoic acid (RA) signaling pathway is often considered an important factor, because RA, the active form of vitamin A that regulates transcription and translation via nuclear RA receptors, plays an important role in the development of embryos and their CNS, and alcohol disturbs retinoid metabolism. This proposal aims to determine if administration of novel retinoid derivatives (RA receptor agonists and antagonists) alleviates prenatal or neonatal alcohol-induced acute neurodegeneration as well as long-lasting abnormalities in neurogenesis, neuroanatomy, and behavior by using mouse models of FASD.
