Effect of Spironolactone of Collagen Synthesis in Pulmonary Arterial Hypertension

螺内酯对胶原合成对肺动脉高压的影响

• 批准号: 8118236
• 负责人: Zeenat Safdar
• 金额: $ 14.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118236
• 关键词: Adult; Advisory Committees; Affect; Age; Aldosterone; Anabolism; Animal Model; Award; Biological Markers; Biology; Biometry; Blood Vessels; Cardiac; Cardiac Catheterization Procedures; Cell Proliferation; Clinical; Clinical Investigator; Clinical Trials; Collagen; Collagen Type I; Data; Deposition; Development; Diagnostic tests; Disease; Diuretics; Doctor of Philosophy; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epidemiology; Ethics; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibrosis; Flow Cytometry; Funding; Gelatinase B; Gender; Goals; Growth Factor; Harvest; Heart Atrium; Heart failure; Human; Hypertrophy; Immunohistochemistry; In Vitro; Knowledge; Laboratories; Lead; Lung; Master' s Degree; Measurement; Mediating; Medicine; Mentors; Mineralocorticoid Receptor; Morbidity - disease rate; Myocardium; Orphan Disease; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phosphorylation; Process; Procollagen; Procollagen Type III; Production; Progressive Disease; Protease Inhibitor; Protein Biosynthesis; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Randomized Clinical Trials; Rattus; Renin-Angiotensin-Aldosterone System; Research Design; Research Personnel; Research Project Grants; Research Proposals; Risk; Role; Scientist; Signal Transduction; Smooth Muscle Myocytes; Spironolactone; Stream; System; Techniques; Testing; Texas; Therapeutic; Time; Tissue Inhibitor of Metalloproteinase-1; Tissues; Training; Training Programs; Transforming Growth Factor beta; Transplantation; Vascular remodeling; Walking; animal data; arteriole; autocrine; base; college; design; functional status; hemodynamics; indexing; monocyte; mortality; multidisciplinary; novel diagnostics; paracrine; peripheral blood; pressure; procollagen type I carboxy terminal peptide; professor; prospective; public health relevance; pulmonary arterial hypertension; pulmonary artery endothelial cell; success

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.

描述(申请人提供)：Zeenat Safdar博士是贝勒医学院的成人肺病专家和医学助理教授。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得克萨斯州最大的肺动脉高压中心，有500多名PAH患者。拟议的教学培训计划专门为Safdar博士设计，包括参加临床科学家培训计划(CSTP；K30资助)，获得临床调查硕士学位，由主要导师和多学科咨询委员会提供正式指导，以及高级生物统计学、研究设计、流行病学和伦理学课程。她将接受以下方面的实践培训：(1)移植肺的免疫组织化学技术，(2)酶联免疫吸附试验、放射免疫分析和流式细胞术，以及(3)从开始到完成的前瞻性随机临床试验的进行和分析。PAH是一种以肺小动脉重构、肥大和胶原沉积为特征的致死性疾病。醛固酮是一种关键的神经激素因子，可加剧血管纤维化。在人的肺动脉内皮细胞中发现了醛固酮的生物合成。我们的初步数据显示，部分PAH受试者循环中的醛固酮水平升高，表明肾素-血管紧张素-醛固酮系统(RAAS)在PAH中调节失调。本实验室12例PAH患者的初步数据显示，胶原标记物(PIIINP)升高与功能状态和血流动力学指标恶化相关。最近的证据表明，醛固酮的促纤维化作用是通过转化生长因子-β-Smad2/3信号通路来实现的。新的初步数据显示，PAH患者外周血单核细胞中磷酸化Smad2的表达增加，提示PAH可能与转化生长因子-β-Smad2/3信号通路的激活有关。总而言之，这些数据强调了研究PAH中的RAAS和下行信令的重要性。具体目标1将检验这样一种假设，即与年龄和性别匹配的正常对照组相比，PAH患者RAAS被激活的程度更大，RAAS/转化生长因子-β/Smad2/3信号的激活是PAH患者较差的临床结果的标志。特殊目标2将在PAH患者中检验两个相互关联的假说：第一，与年龄和性别匹配的对照组相比，将存在循环胶原生物标志物、胶原降解指数和转化生长因子-β/Smad2/3系统的激活；第二，这些水平将与肺血管阻力和循环中的醛固酮水平相关。具体目标3将测试这样一种假设，即用醛固酮受体拮抗剂螺内酯治疗PAH患者，与胶原合成和/或胶原降解的循环生物标志物减少以及转化生长因子-β-Smad2/3信号减少有关。这一奖励将保证Safdar博士发展为独立临床研究员所需的受保护时间。该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：需要获得的知识的重要性肺动脉高压(PAH)是一种进行性疾病，会导致右心衰竭，并在很大程度上影响年轻女性。我们的研究将测试螺内酯(一种利尿剂)在PAH中的临床应用，这可能从根本上改变目前对这种疾病患者的临床治疗方法。此外，我们的研究将在一大群PAH患者中测试新的生物标记物小组，并可能导致新的诊断测试，可能有助于识别有不良预后风险的患者。