Alcohol has been widely consumed historically around the world, as a component of the standard diet, while its misuse undoubtedly leads to a serious assault on human life. The most devastating effect of alcohol misuse is a teratogenic action on fetal development, which causes the permanent birth defects called Fetal Alcohol Spectrum Disorder (FASD). The development of complex circuitry of the brain is particularly vulnerable to alcohol, and therefore alcohol is listed as one of major prenatal risk factors that increase susceptibility to mental illnesses, such as autism and schizophrenia. However, the pathogenetic mechanisms that make the link between fetal alcohol exposure and these disorders that appear later in life are not understood, mostly because it is not possible to detect damaged fetal nerve cells prior to the disease manifestation. The overriding aim of this proposal is 1) to elucidate critical signaling pathway(s) in cortical malformation, which subsequently leads to mental dysfunction in FASD and 2) to provide a potential method of early detection of alcohol-stressed cells. Through our microarray analysis, we have obtained preliminary data that the HSF1 pathway (a stress response pathway) is strongly induced by alcohol in both human and mouse fetal cortical development. We have generated novel mouse in vivo reporter systems that can detect activation of this pathway, so that we can observe the behavior of alcohol-stressed cells in vivo. In order to investigate potential roles of HSF1 in cortical malformation in FASD, we will conduct research using mouse in vivo model. Specifically, during in the mentored phase, I propose to identify critical genes altered by maternal alcohol intake through bioinformatics analysis. During the independent phase, I will 1) observe the pathological characteristics of the cells in which HSF1 is activated under fetal alcohol exposure using fluorescence reporter systems, and 2) investigate the potential role of HSF1 in pathological cortical development in FASD.
Although FASD is the most preventable cause of cognitive disability, its prevalence is estimated to be very high in US. The proposed study will advance our ability for early detection of neuronal damage and our knowledge of underlying molecular mechanisms. Thus it opens the possibility of intervention in the latent period of the patients who are destined to develop mental retardation at later stages in postnatal/adult life.
| Hashimoto-Torii, Kazue; Torii, Masaaki; Fujimoto, Mitsuaki et al. (2014) Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82:560-72 |
| Han, Kihoon; Gennarino, Vincenzo Alessandro; Lee, Yoontae et al. (2013) Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev 27:485-90 |
| Hashimoto-Torii, Kazue; Kawasawa, Yuka Imamura; Kuhn, Alexandre et al. (2011) Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol. Proc Natl Acad Sci U S A 108:4212-7 |
