Effect of Insulin on Estrogen Receptor Alpha Activity in Human Endometrial Cells

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DESCRIPTION (provided by applicant): Dr. Flannery is a board-certified Endocrinologist, who is pursuing a career in translational research with a specific focus on insulin resistance and reproductive pathology. Insulin resistance is an underlying pathology in obesity, the Polycystic Ovary Syndrome (PCOS), and type 2 diabetes mellitus (T2DM). Her immediate research goal is to follow women with insulin resistance, and to determine whether their endometrial dysfunction, such as endometrial hyperplasia and infertility, is a consequence of the metabolic abnormalities occurring in insulin resistance. She is collaborating with Dr. Hugh Taylor of Reproductive Endocrinology to examine a potential mechanism for how insulin may have a direct effect on endometrial cells. Her long-term goal is to contribute to a multi-disciplinary Women's Health research program at the Yale School of Medicine. Over the next five years, Dr. Flannery will spend 85% of her time dedicated to developing research skills with mentorship from Dr. Hugh Taylor and Dr. Robert Sherwin. She will acquire more experience in molecular biology to apply to her project on the endometrium, as well as improving her knowledge in the design, conduct, and analysis of clinical research. She will benefit from the exposure to teaching faculty, association with a peer group, and didactic coursework that is provided through the Yale Center for Clinical Investigation (YCCI) and the Women's Reproductive Health Research (WRHR) Career Development Center. Dr. Flannery proposes to study the effect of insulin on human endometrial cells, using techniques in molecular biology. Specifically, she will examine a potential mechanism for how insulin may augment estrogen action in the endometrium. Preliminary data shows that insulin activates signaling pathways, alters gene transcription, and promotes cellular proliferation of endometrial epithelial cells. She hypothesizes that insulin induces a post-translational modification of the estrogen receptor, resulting in a change in gene transcription. This work will contribute to the understanding of insulin's role as a growth factor n the endometrium. Since the prevalence of obesity and T2DM is increasing in the United States, it is important to determine whether hyperinsulinemia contributes to endometrial pathology such as hyperplasia and infertility. The potential implications of this research include recommendations for weight loss or the use of insulin sensitizers in the treatment of select endometrial pathology. Also, the treatment paradigm for women with T2DM may change to limit exposure to high doses of therapeutic insulin.