A fundamental gap exists in our understanding of how polycystic ovarian syndrome (PCOS) develops. This knowledge is essential to preventing PCOS and co-morbidities such as type 2 diabetes and cardiovascular disease. PCOS patients exhibit a low-grade inflammatory state, which may be triggered by hyperinsulinemia, obesity, or other factors. The proposal's central hypothesis is that low-grade, chronic inflammation associated with PCOS causes ovarian dysfunction. This hypothesis has been formulated from preliminary data produced in the applicant's laboratory and will be tested by pursuing three specific aims: 1) Determine whether inflammation precedes ovarian dysfunction in a potential mouse model of PCOS. 2) Determine whether genetic inhibition of inflammation can prevent the development of PCOS symptoms. 3) Determine whether pharmacological inhibition of inflammation can prevent the development of PCOS symptoms. Under the first aim, a new mouse model of PCOS developed by the applicants will be used to examine the age-dependent onset of androgen excess and inflammation. Under the second aim, mouse strains lacking an inflammatory response will be used to test whether chronic immune system activation leads to PCOS. Finally, the third aim will test whether pharmacological inhibition of a key inflammatory pathway inhibits or treats PCOS. The proposed studies will be the first direct test of whether inflammation plays an essential role in PCOS development using an animal model. The results have the potential to shift current research and clinical practice paradigms by identifying a causative factor in PCOS development and testing a novel pharmacological treatment for the disorder. The findings from this research may help to identify women at risk for PCOS and prevent its development and co-morbidities, thus reducing healthcare costs and extending lives.

Public Health Relevance

These studies have the potential to identify critical factors for the development of polycystic ovarian syndrome and the progression to type 2 diabetes and cardiovascular disease in affected women. This knowledge may provide new prevention and treatment strategies for this common, but poorly understood condition.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD071529-02
Application #
8441506
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Eisenberg, Esther
Project Start
2012-03-08
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$177,390
Indirect Cost
$58,765
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Qiu, Xiaoliang; Dowling, Abigail R; Marino, Joseph S et al. (2013) Delayed puberty but normal fertility in mice with selective deletion of insulin receptors from Kiss1 cells. Endocrinology 154:1337-48