Schistosomiasis Associated Pulmonary Arterial Hypertension

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，该计划将允许主要研究者在肺部医学领域发展学术生涯。主要研究者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，现在将利用环境和合作机会的独特组合来扩展他的科学技能。 该计划将调查与寄生虫病相关的肺动脉高压（PAH），这是一种寄生虫病，影响全球约200万至500万人，主要在巴西和非洲。Rubin Tuder博士是肺血管生物学领域的领导者，他将指导主要研究者的科学发展。Tuder博士是科罗拉多丹佛大学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的免疫病理学家托马斯韦恩博士和加州大学丹佛分校实验性PAH专家库尔特·斯坦马克博士。 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）的啮齿动物模型采用慢性缺氧或野百合碱的内皮细胞毒性，但此类刺激不能准确模拟可能导致所有形式重度PAH发病机制的炎症途径。血吸虫病相关PAH可能涉及炎症细胞和细胞因子与控制肺血管重塑的信号通路的直接相互作用。我们的实验将使用感染寄生虫的小鼠，导致PH。我们假设炎症通过IL-4/IL-13/RELM-1和TGF-2/Smad 2/3途径与血管重塑相关。我们已经观察到IL-13信号上调足以使S恶化。在感染的小鼠和人类中，在病理性肺血管中，与曼氏相关的PH相关的TGF-2信号传导靶点p-Smad 2/3增加。我们的具体目标是确定（1）IL-4/IL-13和（2）TGF-2信号传导是否是血吸虫诱导的PH所必需的。我们将使用外源性抑制剂和敲除小鼠系来调节IL-4、IL-13和TGF-2功能，并分析肺血流动力学、肺血管重塑和炎症信号传导。 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，（2）证明对血吸虫病相关PAH和其他形式的炎性PAH进行治疗干预的机会。 在科罗拉多丹佛大学的肺重症监护部是一个理想的设置，通过从许多资源的专业知识纳入定制的培训计划，培训医生科学家。在大学，司和咨询委员会的水平的环境都是最佳的对齐项目的成功和首席研究员的职业发展。

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.