Effect of Spironolactone of Collagen Synthesis in Pulmonary Arterial Hypertension

描述（由申请人提供）：Zeenat Safdar博士是贝勒医学院的成人肺病学家和医学助理教授。她的长期目标是成为一名富有成效的翻译研究员，参与联邦政府资助的研究项目。贝勒肺动脉高压中心是德克萨斯州最大的PH中心，有500多名PAH患者。Safdar博士专门设计的拟议教学培训计划包括参与临床科学家培训计划（CSTP; K30资助），获得硕士学位，然后获得临床研究博士学位，由主要导师和多学科咨询委员会进行正式指导，以及高级生物统计学，研究设计，流行病学和伦理学课程。她将获得以下方面的实践培训：（1）移植肺的免疫组织化学技术，（2）ELISA，RIA和流式细胞术，以及（3）从开始到完成进行和分析前瞻性随机临床试验。PAH是一种致死性疾病，其特征为肺小动脉重塑伴肥大和胶原沉积。醛固酮是一种重要的神经激素因子，可增强血管纤维化。在人肺动脉内皮细胞中记录了醛固酮的生物合成。我们的初步数据显示，PAH受试者中循环醛固酮水平升高，提示PAH患者的肾素-血管紧张素-醛固酮系统（RAAS）失调。来自我们实验室的12例PAH受试者的初步数据显示，胶原标志物（PIIINP）升高与功能状态和血流动力学数据恶化相关。最近的证据表明，醛固酮促纤维化作用是通过TGF-β-Smad 2/3信号转导介导的。新的初步数据显示，PAH患者外周血单核细胞中磷酸化Smad 2的表达增加，表明PAH可能与TGF-β-Smad 2/3信号级联的激活有关。总的来说，这些数据强调了研究PAH中RAAS和下游信号传导的重要性。具体目标1将检验以下假设：与年龄和性别匹配的正常对照相比，PAH中RAAS的激活程度更高，并且RAAS/TGF-β/Smad 2/3信号传导的激活是PAH受试者临床结局更差的标志物。具体目标2将在PAH患者中检验两个相互关联的假设：首先，与年龄和性别匹配的对照组相比，将存在胶原蛋白的循环生物标志物、胶原蛋白降解指数和TGF-β/Smad 2/3系统的激活;其次，这些水平将与肺血管阻力和醛固酮的循环水平相关。具体目标3将检验以下假设：用醛固酮受体拮抗剂螺内酯治疗PAH受试者与胶原合成和/或胶原降解的循环生物标志物减少以及TGF-β-Smad 2/3信号传导减少相关。该奖项将保证Safdar博士发展成为独立临床研究者所需的受保护时间。本项目的完成将促进我们对PAH疾病恶化的一些机制的理解。 公共卫生相关性：肺动脉高压（PAH）是一种进行性疾病，可导致右心衰竭，主要影响年轻女性。我们的研究将测试螺内酯（一种利尿剂）在PAH中的临床使用，这可能从根本上改变目前治疗这种疾病患者的临床方法。此外，我们的研究将在一大群PAH患者中测试新的生物标志物组合，并可能导致新的诊断测试，可能有助于识别具有不良结局风险的患者。

DESCRIPTION (provided by applicant): Dr. Zeenat Safdar is an adult pulmonologist and assistant professor of Medicine at Baylor College of Medicine. Her long-term goal is to become a productive translational researcher with federally-funded research projects. The Baylor Pulmonary Hypertension Center is the largest PH center in Texas with more than 500 PAH patients. The proposed didactic training program specifically designed for Dr. Safdar includes participation in the Clinical Scientist Training Program (CSTP; K30-funded) leading to a Master's Degree followed by Ph.D in Clinical Investigation, formal mentoring by a primary mentor and a multidisciplinary advisory committee, and courses in advanced biostatistics, research design, epidemiology and ethics. She will obtain hands-on training in (1) immunohistochemistry techniques in transplanted lungs, (2) ELISA, RIA and flow cytometry, and (3) conducting and analyzing a prospective randomized clinical trial from inception to completion. PAH is a lethal disease characterized by remodeling of pulmonary arterioles with hypertrophy and collagen deposition. Aldosterone is a key neurohormonal factor that augments vascular fibrosis. Biosynthesis of aldosterone was documented in human pulmonary artery endothelial cells. Our preliminary data showing an elevation in the circulating aldosterone levels in a subset of PAH subjects suggest that renin-angiotensin- aldosterone system (RAAS) is dysregulated in PAH. Preliminary data in 12 PAH subjects from our laboratory showed that elevated collagen marker (PIIINP) correlated with worse functional status and hemodynamic data. Recent evidence suggests that aldosterone pro-fibrotic effects are mediated through TGF-beta-Smad2/3 signaling. New preliminary data showed increased expression of phosphorylated Smad2 in peripheral blood monocytes from a PAH patient suggesting that PAH may be associated with activation of the TGF-beta- Smad2/3 signaling cascade. Collectively, this data underscore the importance of studying RAAS and down- stream signaling in PAH. Specific Aim 1 will test the hypothesis that the RAAS is activated to a greater degree in PAH as compared to age- and gender-matched normal controls and that activation of RAAS/TGF- beta/Smad2/3 signaling is a marker for worse clinical outcomes in PAH subjects. Specific Aim 2 will test two interrelated hypotheses in PAH patients: first circulating biomarkers of collagen, indices of collagen degrada- tion and activation of theTGF-beta/Smad2/3 system will be present compared to age- and gender-matched controls; second, these levels will correlate with pulmonary vascular resistance and circulating levels of aldos- terone. Specific Aim 3 will test the hypothesis that treatment of PAH subjects with an aldosterone receptor antagonist, spironolactone, is associated with reduction in circulating biomarkers of collagen synthesis and/or collagen degradation and reduced TGF-beta-Smad2/3 signaling. This award will guarantee the protected time needed for Dr. Safdar's development into an independent clinical investigator. Completion of this project will advance our understanding of some of the mechanisms that underlie disease worsening in PAH. PUBLIC HEALTH RELEVANCE: Importance of the Knowledge to be gained Pulmonary arterial hypertension (PAH), a progressive disease, leads to right heart failure and largely affects young females. Our study will test the clinical use of spironolactone (a diuretic) in PAH that may fundamentally change the current clinical approach to patients with this disease. In addition, our study will test new biomarker panel in a large group of PAH patients and may lead to new diagnostic tests that may help identify patients at risk of poor outcome.