Carbon monoxide therapy for severe pulmonary arterial hypertension

描述(由申请人提供)：这份K23申请的PI是一名内科科学家，他的职业生涯专注于为肺动脉高压(PAH)患者开发更好的护理，PAH是一种罕见但虚弱和致命的疾病，目前还没有可用的治疗方法。目前的治疗方案针对导致血管收缩和产生肺血管扩张的细胞功能障碍。虽然这些药物限制了临床恶化和降低肺压力，但它们产生、延缓或逆转坦率的血管重塑的能力是有限的。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而提供强大的细胞保护作用，这些作用对损伤组织的修复和重塑至关重要，包括在PAH中发现的组织。具体地说，吸入CO的外源性输送可以预防和逆转在多种动物模型中已建立的PAH。在一个高度指导的培训计划中，PI将与PI的导师和咨询委员会一起，利用PI提供的惊人专业知识，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。实验假设包括：1)吸入CO可调节PAH患者的生理、细胞和分子通路，从而减轻肺血管重塑；2)外周血单个核细胞(PBMC)可以定义一个分子信号，预测CO的反应性。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，以确定吸入CO在重度PAH患者的标准治疗中的安全性和有效性。具体目标#2将定义PBMCs中的基因组特征，作为重度PAH患者对CO吸入反应的生物标志物。在特定的目标#3中，我们将前瞻性地验证PBMC分子标记作为CO治疗对重度PAH患者的有益反应的生物标志物的实用性。总而言之，这些研究为PI提供了一个出色的课程，使其能够接受基本的临床研究培训，并发展新的、高度转化的方法的技能，这些方法将确定新的靶点和生物标记物，并可能为PAH患者带来更好的治疗选择。 公共卫生相关性：该项目将调查一氧化碳作为一种治疗肺高压的新方法的使用，这种疾病会影响肺的动脉血管，并导致心力衰竭和死亡。我们还将调查遗传标记作为一种工具的作用，以确定可能对一氧化碳治疗有反应的肺动脉高压患者。

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.