Carbon monoxide therapy for severe pulmonary arterial hypertension

描述（由申请人提供）：本K23申请的PI是一名医生-科学家，其职业重点是为肺动脉高压（PAH）患者开发更好的护理，PAH是一种罕见但使人衰弱的致命疾病，目前尚无治愈方法。目前的治疗选择靶向导致血管收缩并产生肺血管舒张的细胞功能障碍。虽然这些药物限制临床恶化和降低肺压，但它们产生、延迟或逆转明显血管重塑的能力有限。越来越多的证据表明，一氧化碳（CO）通过抗炎、抗增殖和抗凋亡作用赋予有效的细胞保护作用，这些作用对损伤组织的修复和重塑至关重要，包括在PAH中发现的那些。具体而言，外源性递送吸入CO可预防和逆转多种动物模型中已建立的PAH。在PI的导师和咨询委员会为PI提供的具有惊人专业知识的高度指导的培训计划中，PI将探索针对PAH病理生物学过程的基于CO的疗法的开发和利用。检验的假设包括：i）吸入CO调节PAH患者的生理、细胞和分子途径，导致肺血管重塑减弱; ii）可以在外周血单核白细胞（PBMC）中定义分子特征，预测CO反应性。为了解决这些假设，在具体目标1中，PI将进行一项I期试验，以确定重度PAH患者在标准治疗中添加吸入性CO的安全性和有效性。具体目标#2将PBMC中的基因组特征定义为重度PAH患者对CO吸入反应性的生物标志物。在具体目标#3中，我们将前瞻性验证PBMC分子特征作为重度PAH患者对CO治疗的有益应答的生物标志物的效用。这些研究为PI提供了出色的课程，使其能够接受临床研究的基本培训，并培养新型、高度转化方法的技能，这些方法将识别新的靶点和生物标志物，并可能为PAH患者带来更好的治疗选择。 公共卫生相关性：该项目将研究使用一氧化碳作为肺动脉高压的新疗法，肺动脉高压是一种影响肺动脉血管并导致心力衰竭和死亡的疾病。我们还将研究遗传标记作为一种工具来识别可能对一氧化碳治疗有反应的肺动脉高压患者的作用。

DESCRIPTION (provided by applicant): The PI of this K23 application is a physician-scientist with a career focus on developing improved care for patient with Pulmonary Arterial Hypertension (PAH), a rare but debilitating and fatal disease for which there is currently no available cure. Current treatment options target the cellular dysfunction that leads to constriction of the vasculature and produce pulmonary vasodilation. While these agents limit clinical deterioration and lower pulmonary pressures, their ability to produce, retard or reverse frank vascular remodeling is limited. Accumulating evidence suggests that carbon monoxide (CO) confers potent cytoprotection via anti-inflammatory, anti-proliferative and anti-apoptotic effects, processes critical for repair and remodeling of injured tissues, including those found in PAH. Specifically, exogenous delivery of inhaled CO prevents and reverses established PAH in multiple animal models. Within a highly mentored training program with staggering expertise available to the PI with the PI's mentor and Advisory Committee, the PI will explore the development and utilization of CO-based therapies that target PAH pathobiological processes. The hypotheses tested include: i) inhaled CO regulates physiologic, cellular and molecular pathways in patients with PAH which result in attenuation of pulmonary vascular remodeling; ii) a molecular signature can be defined in peripheral blood mononuclear leukocytes (PBMCs) which predict CO responsiveness. To address these hypotheses, in Specific Aim #1 the PI will conduct a phase I trial to establish safety and efficacy of inhaled CO when added to standard therapy in patients with severe PAH. Specific Aim #2 will define a genomic signature in PBMCs as biomarkers of responsiveness to CO inhalation in patients with severe PAH. In Specific Aim #3 we will prospectively validate the utility of the PBMC molecular signature as a biomarker of a beneficial response to CO therapy in patients with severe PAH. Together, these studies provide an outstanding curriculum for the PI to receive essential training in clinical research and develop skills in novel, highly translational approaches which will identify novel targets and biomarkers and may lead to better treatment options for patients with PAH. PUBLIC HEALTH RELEVANCE: This project will investigate the use of carbon monoxide as a new treatment for pulmonary hypertension, a disease that affects the arterial blood vessels of the lungs and leads to heart failure and death. We will also investigate the role of genetic markers as a tool to identify patients with pulmonary hypertension likely to respond to carbon monoxide therapy.