Hormonal, Metabolic and Signaling Interactions in PAH

PAH 中的激素、代谢和信号传导相互作用

基本信息

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
项目类别：
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

项目摘要

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.

概括肺动脉高压是一种致命疾病，对数千名患者和家庭。我们的团队已经研究了这种悲剧性疾病已有30多年了，而渐进的知识现在源自这项工作有望大大改善结果。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，雌激素信号传导改变，并在细胞内贩运和胰岛素抵抗，独立工作并协同驱动血管 PAH的功能障碍特征。我们的假设是荷尔蒙和代谢的重点治疗 PAH构成的危险将改善肺血管功能和患者结局。我们的续签计划包括3个项目和2个核心。项目1从周期1继续肺动脉高压）。它探索了从了解直接的途径中获得的令人兴奋的途径性激素对发病机理和性别风险的贡献。我们希望确认雌激素抑制作用他莫昔芬在PAH中是安全和有益的。项目2也从周期1继续（代谢功能肺血管疾病），并从我们对无序重要性的新理解中得出葡萄糖控制，胰岛素抵抗和代谢综合征作为PAH的贡献者。我们希望确认二甲双胍和运动在PAH中是安全和有益的，并测量回复。项目3是新的（PAH响应的基因组和循环预测指标 - 领导者Anna Hemnes MD）我们开发的目标是推进PAH的精密医学，为此我们占有独特的位置。有一个非常未满足的科学依据，以量身定制PAH的治疗方法。我们的长期未来的目标是通过了解每个反应的个体决定因素来优化PAH疗法我们的实验疗法（他莫昔芬，二甲双胍，ACE2）以及批准的代理类（前列环素，，内皮素阻滞剂和磷酸二酯酶抑制剂）。这是转化我们在理解PAH机制方面连续进步的理想时机，因为负责任的途径是由批准的药物（他莫昔芬，二甲双胍）或运动的目标，这些药物是安全且在人类中可以容忍，我们的团队经验丰富和积极性。研究和干预措施都不能在不考虑疾病分子碱的所有方面的情况下最有效，只有在一个高度互动的程序中，我们在这里提出了建议。

项目成果

期刊论文数量（53）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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
影响因子：
0
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 *