Saturday, December 21, 2024
12/21/2024
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is diagnosed by elevated androgens, ovulatory dysfunction, and polycystic ovaries. Women with PCOS have a high prevalence of cardiovascular risk factors (CRFs), such as obesity, insulin resistance (IR), and elevated blood pressure (BP). Effective therapeutic agents to treat CRFs found in PCOS women are limited. The long- term goal is to find effective and safe therapeutic agents to treat CRFs in PCOS women. The Renin-Angiotensin System (RAS), with its classical and nonclassical pathways, is a regulatory system for BP control and metabolic function. The adipose tissue has a fully functional RAS with systemic, paracrine, and autocrine actions. This research proposal will elucidate the role that the adipose classical and nonclassical RAS plays in IR and BP regulation in PCOS. IR is present in lean and obese PCOS women. Plasma adiponectin levels, an insulin- sensitizing hormone, are low in PCOS women, making it an attractive molecular target to decrease IR. The goal of this proposal is to study the interplay between androgens, adiposity, adipose classical and nonclassical RAS, and adiponectin to mediate CRFs in PCOS women. Our central hypothesis is that “hyperandrogenemia has obesity-dependent and -independent effects, leading to increased BP and IR in PCOS. Activation of the classical and inactivation of the nonclassical adipose RAS lead to increased BP. Furthermore, independent of obesity, androgens cause IR via decreased adiponectin levels in PCOS”. This novel and clinically relevant hypothesis will be tested with these aims: Aim 1: To test the hypothesis that obesity as a result of hyperandrogenemia causes an activation of the RAS and increases BP in the PCOS model; Aim 2: To test the hypothesis that an imbalance of the adipose classical and nonclassical RAS in response to hyperandrogenemia leads to increased BP in the PCOS model; Aim 3: To test the hypothesis that decreases in adiponectin in response to hyperandrogenemia lead to obesity-independent IR in the PCOS model. We will test this hypothesis using an innovative combination of gold-standard methods to measure BP, IR, fat distribution and function, and systemic and adipose RAS peptides in two well-characterized, clinically relevant models of PCOS and a 3D adipocytes cell culture. The proposed research is significant because it will shed light on the androgens- mediated mechanisms and the interplay between obesity, the classical and nonclassical RAS, and adipokines in the pathophysiology of the CRFs in PCOS women. Moreover, this study will identify potential new therapeutic options to ameliorate CRFs in PCOS women.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).