Schistosomiasis Associated Pulmonary Arterial Hypertension

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，该计划将允许首席研究员在肺医学领域发展学术生涯。首席研究员已经完成了内科住院医师培训计划和肺病和重症监护医学的奖学金培训，现在将利用独特的环境和合作机会来扩展他的科学技能。该计划将调查血吸虫病相关肺动脉高压（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军人物，他将指导首席研究员的科学发展。Tuder博士是科罗拉多大学丹佛分校肺重症医学部门的研究主任。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多环芳烃专家库尔特·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多环芳烃。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，要么采用单罗塔碱对内皮细胞产生毒性，但这种刺激并不能准确地模拟可能导致所有形式的严重PAH发病机制的炎症途径。血吸虫病相关的多环芳烃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寄生虫导致ph的小鼠。我们假设炎症通过IL-4/IL-13/RELM-1和TGF-2/Smad2/3途径与血管重塑有关。我们观察到IL-13信号的上调足以使曼氏梭菌相关的PH恶化，TGF-2信号靶点p-Smad2/3在感染小鼠和人的病理性肺血管中升高。我们的具体目的是确定(1)IL-4/IL-13和(2)TGF-2信号是否对血吸虫诱导的ph是必要的。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。确定血吸虫病感染导致血管重塑的机制将(1)提供对肺血管炎症和重塑之间相互作用的深入了解，这也参与了其他形式的多环芳烃的发病机制；(2)为血吸虫病相关的多环芳烃和其他形式的炎症性多环芳烃的治疗干预提供机会。科罗拉多大学丹佛分校的肺重症监护室通过将许多资源的专业知识整合到定制的培训计划中，是培训内科科学家的理想场所。大学、学部和咨询委员会层面的环境都是为了项目的成功和首席研究员的职业发展而优化的。

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.