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Principal Investigator: Anna R Hemnes
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2021
Award: $1,678,313
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Pulmonary Arterial Hypertension is a lethal disease with devastating impact on thousands of patients and
families. Our team has studied this tragic disease for more than 3 decades and the progressive knowledge
derived from that work now promises to greatly improve outcomes.
Our overall theme is to develop and apply therapies which are directed against mechanisms central to
Pulmonary Arterial Hypertension (PAH). Our studies indicate that altered estrogen signalling, and defects in
intracellular trafficking and insulin resistance, work independently and in concert to drive the vascular
dysfunction characteristic of PAH. Our hypothesis is that focused treatment of the hormonal and metabolic
derangements which underlie PAH will improve pulmonary vascular function and patient outcomes.
Our renewal program includes 3 Projects and 2 Cores. Project 1 is continued from cycle 1 (Sex Hormones in
Pulmonary Arterial Hypertension). It explores exciting avenues derived from understanding the direct
contribution of sex hormones to pathogenesis and risk by gender. We expect to confirm that estrogen inhibition
with tamoxifen is safe and beneficial in PAH. Project 2 is also continued from cycle 1 (Metabolic Function in
Pulmonary Vascular Disease) and emerges from our new understanding of the importance of disordered
glucose control, insulin resistance and the metabolic syndrome as contributors to PAH. We expect to confirm
that metformin and exercise are safe and beneficial in PAH, and to measure individual patient determinants of
response. Project 3 is new (Genomic and Circulating Predictors of PAH response - Leader Anna Hemnes MD)
which we developed with the goal to advance precision medicine in PAH, for which we are uniquely positioned.
There exists a great unmet need for a scientific basis to tailor the treatment approach for PAH. Our longterm
future goal is to optimize PAH therapy by understanding the individual determinants of response, for each of
our experimental therapies (tamoxifen, metformin, ACE2) as well as approved agent classes (prostacyclins,
endothelin blockers, and phosphodiesterase inhibitors).
This is an ideal time to translate our successive progress in understanding PAH mechanisms, because the
responsible pathways are targeted by approved drugs (tamoxifen, metformin) or exercise, which are safe and
tolerable in humans, and our team is experienced and motivated. Neither the studies nor the interventions can
be most effective without considering all aspects of the molecular bases of the disease, which is only possible
in a highly interactive program such as that we propose here.
Terms: <3'5'-cyclic ester of AMP><ACE2><Accelerometer><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Affect><Age><Amino Acids><Androgenic Agents><Androgenic Compounds><Androgens><Anti-Estrogens><Antiphosphodiesterases><Aquadiol><Biology><Blinded><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Vessels><Cardiac><Cardiac Catheterization><Cardiac Catheterization Procedures><Causality><Cell Communication and Signaling><Cell Signaling><Characteristics><Clinical><Consumption><Coupled><Cyclic AMP><DNA><Defect><Deoxyribonucleic Acid><Diagnosis><Dimenformon><Dimethylbiguanidine><Dimethylguanylguanidine><Diogyn><Diogynets><Disease><Disorder><Drugs><Echocardiogram><Echocardiography><Endothelin><Endothelium-Derived Vasoconstrictor Factors><Enrollment><Estrace><Estradiol><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Antagonists><Estrogen Receptors><Estrogens><Estrone><Etiology><Exercise><Experimental Therapies><Family><Fatty Acids><Future><Gender><Gene Transcription><Gene variant><Genetic><Genetic Diversity><Genetic Transcription><Genetic Variation><Genomics><Goals><Gonadal Steroid Hormones><H+ element><Heart Catheterization><Heart Catheterization Procedure><Hormonal><Human><Humulin R><Hydrogen Ions><Individual><Insertion of catheter into heart chamber><Insulin><Insulin Resistance><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigational Therapies><Investigational Treatments><Isoprostanes><Knowledge><Legal patent><Lipids><Longitudinal Studies><Lung><Lung Respiratory System><MR Spectroscopy><Magnetic Resonance Spectroscopy><Measures><Mediator><Mediator of Activation><Mediator of activation protein><Medical Records><Medication><Metabolic><Metabolic syndrome><Metformin><Mitochondria><Modern Man><Molecular><Muscle Fatigue><Muscle function><Muscular Fatigue><N,N-dimethyl-imidodicarbonimidic diamide><Novolin R><Ovocyclin><Ovocylin><Oxidative Stress><PET><PET Scan><PET imaging><PETSCAN><PETT><Patents><Pathogenesis><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology><Phenotype><Phosphodiesterase Antagonists><Phosphodiesterase Inhibitors><Phosphoric Diester Hydrolase Inhibitors><Placebos><Plasma><Plasma Serum><Position><Positioning Attribute><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Predict drug response><Production><Progynon><Prostacyclins><Prostaglandins I><Proteomics><Protons><Pulmonary Hypertension><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Rad.-PET><Randomized><Receptor Protein><Regular Insulin><Regulation><Reticuloendothelial System, Serum, Plasma><Risk><Safety><Severity of illness><Sex Hormones><Sex Steroid Hormones><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal 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damage><oxidative injury><pathway><patient specific therapies><patient specific treatment><peripheral blood><physical activity intervention><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><precision medicine><precision-based medicine><predict clinical outcome><predictor of clinical outcome><primary end point><primary endpoint><programs><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><randomisation><randomization><randomly assigned><receptor><receptor density><receptor expression><response><sex steroid><sham therapy><tailored medical treatment><tailored therapy><tailored treatment><therapeutically effective><trafficking><transcriptome sequencing><trial comparing><unique treatment><vascular><vascular dysfunction><vasculopathy>