Effect of Spironolactone of Collagen Synthesis in Pulmonary Arterial Hypertension

简介（由申请人提供）：Zeenat Safdar博士是贝勒医学院的一名成人肺科专家和医学助理教授。她的长期目标是在联邦资助的研究项目中成为一名富有成效的转化研究人员。贝勒肺动脉高压中心是德克萨斯州最大的肺动脉高压中心，有500多名肺动脉高压患者。专为Safdar博士设计的拟议教学培训计划包括参加临床科学家培训计划（CSTP； k30资助），获得临床研究硕士学位和博士学位，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。多环芳烃是一种以肺小动脉重塑、肥厚和胶原沉积为特征的致死性疾病。醛固酮是增加血管纤维化的关键神经激素因子。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，一部分PAH受试者的循环醛固酮水平升高，这表明肾素-血管紧张素-醛固酮系统（RAAS）在PAH中失调。我们实验室对12名PAH受试者的初步数据显示，胶原蛋白标志物（PIIINP）升高与较差的功能状态和血流动力学数据相关。最近的证据表明醛固酮的促纤维化作用是通过tgf - β - smad2 /3信号介导的。新的初步数据显示PAH患者外周血单核细胞磷酸化Smad2表达增加，提示PAH可能与tgf - β - Smad2/3信号级联的激活有关。总的来说，这些数据强调了研究paah中RAAS和下游信号传导的重要性。特异性目标1将验证假设：与年龄和性别匹配的正常对照相比，PAH患者的RAAS被激活的程度更大，RAAS/TGF- β /Smad2/3信号的激活是PAH患者临床结果更差的标志。特异性目标2将在PAH患者中测试两个相互关联的假设：与年龄和性别匹配的对照组相比，胶原的第一循环生物标志物，胶原降解指数和tgf - β /Smad2/3系统的激活将存在；其次，这些水平将与肺血管阻力和循环中的醛酮水平相关。特异性目的3将验证假设，即使用醛固酮受体拮抗剂螺内酯治疗多环芳烃受试者，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 - smad2 /3信号减少有关。这笔奖金将保证萨夫达尔博士发展成为一名独立临床研究者所需的受保护时间。该项目的完成将促进我们对多环芳烃疾病恶化的一些机制的理解。

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.