Schistosomiasis Associated Pulmonary Arterial Hypertension

描述(由申请人提供)：这份建议书描述了一项为期5年的培训计划，该计划将允许首席研究人员在肺部医学领域发展学术生涯。首席研究员已经完成了内科的结构化住院医师培训计划以及肺部和重症监护医学的奖学金培训，现在将利用独特的环境和协作机会来扩展他的科学技能。该项目将研究血吸虫病相关性肺动脉高压(PAH)，这是一种影响全球约200万至500万人的寄生虫病，主要在巴西和非洲。鲁宾·图德博士是肺血管生物学领域的领军人物，他将指导首席研究员的科学发展。图德博士是科罗拉多大学丹佛分校肺部重症监护医学部的研究主任。其他合作者包括美国国立卫生研究院著名免疫病理学家Thomas Wynn博士和加州大学丹佛分校实验PAH专家Kurt Stenmark博士。我们的总体研究目标是阐明宿主对曼氏血吸虫的反应如何导致PAH。大多数实验性肺动脉高压(PH)的啮齿动物模型要么采用慢性缺氧，要么使用野百合碱对内皮细胞的毒性，但这种刺激不能准确地模拟可能导致所有形式的严重PAH发病的炎症途径。血吸虫病相关的PAH可能涉及炎症细胞和细胞因子与控制肺血管重构的信号通路的直接相互作用。我们的实验将使用感染了这种寄生虫的小鼠，导致PH。我们假设炎症通过IL-4/IL-13/RELM-1和转化生长因子-2/Smad2/3途径与血管重塑有关。我们观察到IL-13信号的上调足以加重曼氏葡萄球菌相关的PH，并且在感染的小鼠和人的病理性肺血管中，转化生长因子-2信号靶点p-Smad2/3都增加。我们的具体目的是确定(1)IL-4/IL-13和(2)转化生长因子-2信号在血吸虫诱导的PH中是否是必需的。我们将使用外源性抑制剂和基因敲除小鼠来调节IL-4、IL-13和转化生长因子-2的功能，并分析肺血流动力学、肺血管重塑和炎症信号。确定血吸虫病感染导致血管重塑的机制将(1)深入了解肺血管炎症和重塑之间的相互作用，这也参与了其他形式的PAH的发病机制，以及(2)展示了治疗血吸虫病相关的PAH和其他形式的炎症性PAH的机会。科罗拉多大学丹佛分校的肺危重护理部门通过将多种资源的专业知识整合到定制的培训计划中，是培训医生和科学家的理想环境。为了项目的成功和首席调查员的职业发展，大学、司和咨询委员会一级的环境都得到了最佳的协调。 公共卫生相关性：血吸虫病是全球第三大常见寄生虫病，也是导致肺动脉高压(PAH)的最常见原因之一，PAH是一种进行性呼吸急促和心力衰竭的破坏性疾病。血吸虫病是如何引起PAH的尚不清楚。我们正在研究感染血吸虫病的小鼠，以确定疾病发生的原因，并为血吸虫病、血吸虫病相关的PAH以及发达国家更常见的PAH的其他原因提供治疗可能性。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program which will allow the principal investigator to develop an academic career in Pulmonary Medicine. The principal investigator has completed a structured residency training program in Internal Medicine and fellowship training in Pulmonary and Critical Care Medicine, and will now utilize a unique combination of environment and collaborative opportunities to expand his scientific skills. The program will investigate schistosomiasis-associated pulmonary arterial hypertension (PAH), a parasitic disease which affects approximately 2-5 million people worldwide, primarily in Brazil and Africa. Dr. Rubin Tuder, a leader in the field of pulmonary vascular biology, will mentor the principal investigator's scientific development. Dr. Tuder is the Director of Research in the Pulmonary-Critical Care Medicine Division at the University of Colorado Denver. Other collaborators include Dr. Thomas Wynn, a renowned immunopathologist at the NIH and Dr. Kurt Stenmark, an expert in experimental PAH at UC Denver. Our overall research goal is to elucidate how the host response to Schistosoma mansoni results in PAH. Most rodent models of experimental pulmonary hypertension (PH) employ either chronic hypoxia or endothelial cell toxicity with monocrotaline, but such stimuli do not accurately model the inflammatory pathways likely contributory to the pathogenesis of potentially all forms of severe PAH. Schistosomiasis-associated PAH may involve the direct interplay of inflammatory cells and cytokines with signaling pathways that control pulmonary vascular remodeling. Our experiments will use mice infected with the parasite, resulting in PH. We hypothesize inflammation is linked with vascular remodeling by the IL-4/IL-13/RELM-1 and TGF-2/Smad2/3 pathways. We have observed IL-13 signaling upregulation is adequate to worsen S. mansoni-associated PH, and the TGF-2 signaling target p-Smad2/3 is increased in pathologic pulmonary vessels in both infected mice and humans. Our specific aims are to determine if (1) IL-4/IL-13 and (2) TGF-2 signaling are necessary for Schistosoma- induced PH. We will use exogenous inhibitors and knockout mouse lines to modulate IL-4, IL-13 and TGF-2 function, and analyze pulmonary hemodynamics, pulmonary vascular remodeling, and inflammatory signaling. Determining the mechanism by which schistosomiasis infection leads to vascular remodeling will (1) provide insight into the interplay between pulmonary vascular inflammation and remodeling, which also participates in the pathogenesis of other forms of PAH, and (2) demonstrate opportunities for therapeutic intervention in schistosomiasis-associated PAH and other forms of inflammatory PAH. The Pulmonary-Critical Care Division at the University of Colorado Denver is an ideal setting for training physician-scientists through the incorporation of expertise from many resources into a customized training program. The environments at the level of the University, Division, and Advisory Committees are all optimally aligned for the success of the project and for the career development of the principal investigator. PUBLIC HEALTH RELEVANCE: Schistosomiasis is the third most common parasitic disease worldwide and one of the most common causes of pulmonary arterial hypertension (PAH), a devastating condition of progressive shortness of breath and heart failure. How schistosomiasis causes PAH is unknown. We are studying mice infected with schistosomiasis to determine why the disease occurs and provide insight into treatment possibilities for schistosomiasis, schistosomiasis-associated PAH, and other causes of PAH more common in developed countries.