ARRA: Developmental regulation of estrogen receptor alpha by spigenetic modification

With support from the National Science Foundation, I will conduct a three-year study investigating the molecular mechanisms by which critical genes are regulated in the developing mouse brain. The gene of interest in the current study is estrogen receptor-alpha. Estrogen exposure during development is critical for establishing long-term structural and functional aspects of the brain. Estrogen acts through intracellular receptors that mediate its action. Estrogen receptor gene expression is developmentally regulated and this proposal will explore the novel molecular mechanisms of this regulation in the brain. In particular, the effects of epigenetic modification of DNA by methylation will be examined in a mouse animal model. Techniques such as in situ hybridization, real-time polymerase chain reaction and chromatin immunoprecipitation will be employed. The overall intellectual merit of this proposal will be derived from our enhanced understanding of the regulation of gene expression in the brain at different developmental stages, as these changes can have long-lasting consequences in brain function in adulthood. This proposal combines the fields of neuroendocrinology with the rapidly growing field of epigenetics. This is a new and unique area of investigation. In addition to the answering fundamental questions in the field of developmental neuroscience, the impact of this work will be enhanced by the involvement of multiple undergraduate and graduate students over the course of the study and provide a fundamental scientific background to these students. The University of Kentucky is the largest university in the state of Kentucky and serves the eastern half of the state including underrepresented geographical areas such as Appalachia. Seventy seven percent of undergraduate and graduate students are from the state of Kentucky. Over the past six years I have trained 2 high school, 9 undergraduate and 3 graduate students in my laboratory and I am active in mentoring students from the Agricultural Biotechnology program in the College of Agriculture as well the as Biology Department in the College of Arts and Sciences. I have also taken a student from nearby Midway College, which is a small, predominantly female undergraduate liberal arts institution. Additionally, high school students from the Math, Science and Technology Center program in the public school system have participated in research in my laboratory. Of the students I have mentored, 11 were from Kentucky, including one from a rural county in eastern Kentucky. Only 33% of the adults in her county have a high school education and she will be the first person to receive a PhD in a biomedical field. All in all, support for these students is critical to encouraging science to a population of students who do not always have the strongest of scientific backgrounds. The students will be involved in all aspects of this project from performing experiments to presenting the findings. All students will be encouraged to present their data at University events such as the "Spotlight on Undergraduate Research Day" and the annual Reproductive Sciences and Women's Health Symposium as well as at other regional and national meetings. As a laboratory, we also participate in community events such as those associated with Brain Awareness Week with the Society for Neuroscience. We interact with the public to educate children and parents alike to importance of understanding how their brains work. Additionally I have a long-standing commitment as a science fair judge in the Fayette County School system. I encourage my students to participate as judges as well. Many students at the University of Kentucky come from a disadvantaged background, especially in terms of science education. Thus, the students trained under this proposal will be exposed to novel and exciting research and will help stimulate the careers of several budding young scientists.