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.

Public Health Relevance

Endometrial dysfunction commonly occurs in women with obesity, Polycystic Ovary Syndrome or Type 2 Diabetes Mellitus. These women have high levels of insulin, and insulin may contribute to irregular bleeding, implantation failure, miscarriage, endometrial hyperplasia, and endometrial carcinoma. This research looks at one way in which insulin may affect endometrial tissue.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD071010-03
Application #
8691432
Study Section
Developmental Biology Subcommittee (CHHD)
Program Officer
Yoshinaga, Koji
Project Start
2012-08-21
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Flannery, Clare A; Fleming, Andrew G; Choe, Gina H et al. (2016) Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium. Endocrinology 157:3699-3708
Flannery, Clare A; Rowzee, Anne M; Choe, Gina H et al. (2016) Development of a Quantitative PCR Assay for Detection of Human Insulin-Like Growth Factor Receptor and Insulin Receptor Isoforms. Endocrinology 157:1702-8
Flannery, Clare A; Saleh, Farrah L; Choe, Gina H et al. (2016) Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma. J Clin Endocrinol Metab 101:2883-91
Ghazal, Sanaz; McKinnon, Brett; Zhou, Jichun et al. (2015) H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol Med 7:996-1003
Han, Christina S; Herrin, Melissa A; Pitruzzello, Mary C et al. (2015) Glucose and metformin modulate human first trimester trophoblast function: a model and potential therapy for diabetes-associated uteroplacental insufficiency. Am J Reprod Immunol 73:362-71
Karalok, Hakan Mete; Aydin, Ebru; Saglam, Ozlen et al. (2014) mRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium. J Clin Endocrinol Metab 99:E2610-9
Gao, Yuan; Wu, Fuju; Zhou, Jichun et al. (2014) The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells. Nucleic Acids Res 42:13799-811