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Principal Investigator: LICY LORENA YANES CARDOZO
Organization: UNIVERSITY OF MISSISSIPPI MED CTR
Fiscal Year: 2024
Award: $700,565
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <3-D><3-Dimensional><3D><3D cell culture><3D culture><5 alpha-Dihydrotestosterone><5-alpha-DHT><ACE2><ACRP30 protein><Address><Adipocytes><Adipose Cell><Adipose tissue><Adverse effects><Affect><Age><Agonist><Androgenic Agents><Androgenic Compounds><Androgens><Androstanolone><AngII><Angiotensin AT1 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin II Type 1 Receptor><Angiotensins><Animal Model><Animal Models and Related Studies><Applications Grants><Autocrine Systems><BP control><BP homeostasis><BP management><BP reduction><BP regulation><Blood Plasma><Blood Pressure><Body Weight decreased><CD143 Antigens><Carboxycathepsin><Cardiovascular Diseases><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Common Rat Strains><Control Groups><Data><Diagnosis><Dihydrotestosterone><Dipeptidyl Peptidase A><Dysfunction><Enacard><Enalapril><Endocrine Diseases><Endocrine Diseases and Manifestations><Endocrine Gland Secretion><Endocrine System Diseases><Enzyme Inhibition><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Female><Functional disorder><Goals><Grant Proposals><Health><High Prevalence><Hormones><Human><Humulin R><Hyperandrogenemia><Image><Impairment><In Vitro><Insulin><Insulin Resistance><Intracellular Communication and Signaling><KO mice><Kininase A><Kininase II><Knock-out Mice><Knockout Mice><Knowledge><Laboratories><Lead><Leanness><Lipocytes><Mature Lipocyte><Mature fat cell><Measurement><Measures><Mediating><Metabolic><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Target><Murine><Mus><Novolin R><Null Mouse><Obesity><Pathway interactions><Pb element><Peptides><Peptidyl-Dipeptidase A><Physiologic><Physiological><Physiopathology><Plasma><Plasma Serum><Play><Polycystic Ovarian Disease><Polycystic Ovarian Syndrome><Polycystic Ovary Syndrome><Rat><Rats Mammals><Rattus><Receptor Protein><Receptor, Angiotensin, Type 1><Regular Insulin><Renin-Angiotensin System><Renitec><Renitek><Research><Research Proposals><Reticuloendothelial System, Serum, Plasma><Role><Sclerocystic Ovarian Degeneration><Sclerocystic Ovary Syndrome><Signal Transduction><Signal Transduction Systems><Signaling><Stanolone><System><Testing><Testosterone><Therapeutic Agents><Therapeutic Androgen><Therapeutic Androstanolone><Therapeutic Hormone><Therapeutic Testosterone><Thinness><Trans-Testosterone><Translating><Vasotec><Visceral><Weight Gain><Weight Increase><Weight Loss><Weight Reduction><Woman><adipocyte complement-related protein 30-kDa><adipocyte, C1q and collagen domain containing protein><adipocytokines><adipokines><adiponectin><adipose><adiposity><aged><ages><androgen excess><angiotensin II type I receptor><angiotensin converting enzyme 2><angiotensin converting enzyme II><apM-1 protein><apM1 (adipose-specific) protein><arm><autocrine><biological signal transduction><blood pressure control><blood pressure elevation><blood pressure homeostasis><blood pressure management><blood pressure reduction><blood pressure regulation><body weight gain><body weight increase><body weight loss><cardiometabolic><cardiometabolism><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular risk><cardiovascular risk factor><cell culture><cell cultures><clinical relevance><clinically relevant><compare to control><comparison control><corpulence><elevated blood pressure><endocrine disorder><feeding><heavy metal Pb><heavy metal lead><imaging><implantation><improved><in vivo><increase in blood pressure><increased blood pressure><innovate><innovation><innovative><insulin resistant><insulin tolerance><lower BP><lower blood pressure><lowers blood pressure><male><model of animal><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ovarian dysfunction><ovulatory dysfunction><paracrine><pathophysiology><pathway><pharmacologic><polycystic ovary><polycystic ovary disease><polycystic ovary disorder><prevent><preventing><receptor><reduce BP><reduce blood pressure><reduction in BP><reduction in blood pressure><regulate BP><regulate blood pressure><reproductive><response><social role><subcutaneous><subdermal><therapeutically effective><three dimensional><three dimensional cell culture><white adipose tissue><wt gain><wt-loss><yellow adipose tissue>