Hormonal, Metabolic and Signaling Interactions in PAH

PAH 中的激素、代谢和信号传导相互作用

• 批准号: 10250450
• 负责人: Anna R Hemnes
• 金额: $ 167.83万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250450
• 关键词: ACE2; Accelerometer; Affect; Age; Amino Acids; Androgens; Biology; Blinded; Blood; Blood Vessels; Cardiac; Cardiac Catheterization Procedures; Characteristics; Clinical; Consumption; Coupled; Cyclic AMP; DNA; Defect; Diagnosis; Disease; Echocardiography; Endothelin; Enrollment; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrogens; Estrone; Etiology; Exercise; Family; Fatty Acids; Future; Gender; Genetic; Genetic Transcription; Genetic Variation; Genomics; Goals; Gonadal Steroid Hormones; Hormonal; Human; Individual; Insulin; Insulin Resistance; Intervention; Investigational Therapies; Isoprostanes; Knowledge; Legal patent; Lipids; Longitudinal Studies; Lung; Magnetic Resonance Spectroscopy; Measures; Mediator of activation protein; Medical Records; Metabolic; Metabolic syndrome; Metformin; Mitochondria; Molecular; Muscle Fatigue; Muscle function; Oxidative Stress; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphodiesterase Inhibitors; Placebos; Plasma; Positioning Attribute; Positron-Emission Tomography; Production; Prostaglandins I; Proteomics; Protons; Pulmonary Hypertension; Randomized; Regulation; Risk; Safety; Severity of illness; Signal Transduction; Skeletal Muscle; Tamoxifen; Testing; Time; Tracer; Translating; Urine; Variant; Vascular Diseases; Ventricular Function; Woman; Work; aggressive therapy; base; blood glucose regulation; capillary bed; clinical predictors; cohort; density; drug response prediction; endothelial stem cell; exercise capacity; exercise intervention; experience; genetic predictors; genetic variant; improved; improved outcome; individual patient; individualized medicine; mHealth; metabolomics; mouse model; muscle strength; novel; novel therapeutic intervention; optimal treatments; oxidant stress; oxidative damage; peripheral blood; precision medicine; predict clinical outcome; primary endpoint; programs; pulmonary arterial hypertension; receptor; receptor density; receptor expression; response; therapeutically effective; trafficking; transcriptome sequencing; trial comparing

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.

总结 肺动脉高压是一种致命的疾病，对成千上万的患者造成毁灭性的影响， 家庭我们的团队已经研究这种悲惨的疾病超过30年， 从这项工作中获得的成果现在有望大大改善成果。 我们的总体主题是开发和应用针对核心机制的疗法， 肺动脉高压（PAH）。我们的研究表明，雌激素信号的改变， 细胞内运输和胰岛素抵抗，独立地工作，并协同驱动血管 PAH的功能障碍特征。我们的假设是，集中治疗激素和代谢 肺动脉高压的基础紊乱将改善肺血管功能和患者结局。 我们的更新计划包括3个项目和2个核心。项目1是从第1周期（性激素， 肺动脉高压）。它探索了令人兴奋的途径，从了解直接 性激素对发病机制和性别风险的贡献。我们希望证实雌激素抑制 与他莫昔芬联合治疗PAH是安全和有益的。项目2也是从周期1继续（代谢功能， 肺血管疾病），并出现了我们的新认识的重要性， 血糖控制、胰岛素抵抗和代谢综合征是PAH的促成因素。我们希望确认 二甲双胍和运动在PAH中是安全和有益的，并测量个体患者的 反应项目3是新的（PAH应答的基因组和循环预测因子-负责人安娜Hemnes MD） 我们开发的目标是推进PAH的精准医学，我们在这方面具有独特的优势。 目前存在着一个很大的未满足的需求，需要一个科学的基础来调整PAH的治疗方法。我们的长期 未来的目标是通过了解反应的个体决定因素来优化PAH治疗， 我们的实验性疗法（他莫昔芬、二甲双胍、ACE 2）以及批准的药物类别（前列环素， 内皮素阻断剂和磷酸二酯酶抑制剂）。 这是一个理想的时间来转化我们在理解PAH机制方面的连续进展，因为 负责的途径是通过批准的药物（他莫昔芬，二甲双胍）或运动，这是安全的， 我们的团队经验丰富，积极主动。无论是研究还是干预， 在不考虑疾病分子基础的所有方面的情况下最有效， 在一个高度互动程序中，比如我们在这里提出的。

项目成果

A potential adverse role for leptin and cardiac leptin receptor in the right ventricle in pulmonary arterial hypertension: effect of metformin is BMPR2 mutation-specific.

• DOI: 10.3389/fmed.2023.1276422
• 发表时间: 2023
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Talati M;Brittain E;Agrawal V;Fortune N;Simon K;Shay S;Zeng X;Freeman ML;West J;Hemnes A
• 通讯作者: Hemnes A

Integrative Omics to Characterize and Classify Pulmonary Vascular Disease.

• DOI: 10.1016/j.ccm.2020.10.001
• 发表时间: 2021-03
• 期刊: Clinics in chest medicine
• 影响因子: 5.7
• 作者: Leopold JA;Hemnes AR
• 通讯作者: Hemnes AR

Echocardiographic assessment of the right heart in mice.

• DOI: 10.3791/50912
• 发表时间: 2013-11-27
• 期刊: Journal of visualized experiments : JoVE
• 作者: Brittain E;Penner NL;West J;Hemnes A
• 通讯作者: Hemnes A

Assessing the Accuracy of Estimated Lipoprotein(a) Cholesterol and Lipoprotein(a)-Free Low-Density Lipoprotein Cholesterol.

• DOI: 10.1161/jaha.121.023136
• 发表时间: 2022-01-18
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Zheng, Weili;Chilazi, Michael;Park, Jihwan;Sathiyakumar, Vasanth;Donato, Leslie J.;Meeusen, Jeffrey W.;Lazo, Mariana;Guallar, Eliseo;Kulkarni, Krishnaji R.;Jaffe, Allan S.;Santos, Raul D.;Toth, Peter P.;Jones, Steven R.;Martin, Seth S.
• 通讯作者: Martin, Seth S.

Mortality in Pulmonary Arterial Hypertension in the Modern Era: Early Insights From the Pulmonary Hypertension Association Registry.

• DOI: 10.1161/jaha.121.024969
• 发表时间: 2022-05-03
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Chang KY;Duval S;Badesch DB;Bull TM;Chakinala MM;De Marco T;Frantz RP;Hemnes A;Mathai SC;Rosenzweig EB;Ryan JJ;Thenappan T;PHAR Investigators *
• 通讯作者: PHAR Investigators *