Carbon monoxide therapy for severe pulmonary arterial hypertension

描述（由申请人提供）：本次K23申请的PI是一名医师兼科学家，其职业重点是为肺动脉高压（PAH）患者开发改进的护理，PAH是一种罕见但使人衰弱和致命的疾病，目前尚无治愈方法。目前的治疗方案针对导致血管收缩和产生肺血管舒张的细胞功能障碍。虽然这些药物限制了临床恶化和降低肺压，但它们产生、延缓或逆转血管重构的能力是有限的。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，包括在多环芳烃中发现的那些。具体而言，在多种动物模型中，外源性吸入一氧化碳可预防和逆转已建立的多环芳烃。在一个高度指导的培训项目中，PI将与PI的导师和咨询委员会一起获得惊人的专业知识，PI将探索针对PAH病理生物学过程的基于co的治疗方法的开发和利用。所检验的假设包括：1)吸入一氧化碳调节多环芳烃患者的生理、细胞和分子途径，导致肺血管重构的衰减；ii)可以在外周血单核白细胞（PBMCs）中定义预测CO反应的分子特征。为了解决这些假设，在Specific Aim #1中，PI将进行I期试验，以确定将吸入一氧化碳添加到严重PAH患者的标准治疗中时的安全性和有效性。特异性目标#2将定义pbmc的基因组特征，作为严重PAH患者对CO吸入反应性的生物标志物。在Specific Aim #3中，我们将前瞻性地验证PBMC分子标记作为严重PAH患者CO治疗有益反应的生物标志物的效用。总之，这些研究为PI提供了一个出色的课程，以接受临床研究的基本培训，并开发新的、高度转化的方法技能，这些方法将确定新的靶点和生物标志物，并可能为PAH患者提供更好的治疗选择。

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.