Quantifiable biomarkers of vasodilator therapeutic response in children with IPAH

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）生物标志物发现和验证以及特定的挑战主题03-HL-101：鉴别和验证血液、血管、心脏和呼吸道功能障碍的诊断和治疗反应的临床相关、可定量生物标志物。儿童或成人特发性（原发性）肺动脉高压（IPAH）是一种进行性和致死性疾病，其特征是病因不明的肺动脉压力持续升高。血管扩张剂是治疗的主要药物，然而20-30%的儿童对血管扩张剂无反应，无反应者预后不良。由于病理生物学未知，血管扩张剂治疗具有显著的发病率和成本（约50，000美元/年），并且缺乏血管扩张剂疗效的标志物，我们的长期目标是确定儿童IPAH的血清、诊断和预后标志物，以改善长期结局。为了实现这一目标，我们优化了一种深入的蛋白质组学方法，使用丰富的蛋白质去除结合完整的蛋白质分离方法和质谱法来鉴定肺动脉高压儿童中即使是低丰度的血清蛋白。在我们使用IPAH儿童纵向血清样本的初步数据中，我们已经确定了IPAH儿童血管扩张剂治疗后许多血清蛋白的显著变化。每年约翰霍普金斯学院直接在马里兰州产生约100亿美元的经济活动，比2002年产生的70亿美元增加了43%，相当于今天该州经济中的每24美元。2008年，约翰霍普金斯机构提供了45，000个工作岗位，自2002年以来每年创造700个新工作岗位。约翰霍普金斯学院直接和间接地为马里兰州提供了10万多个工作岗位，是该州每29个工作岗位中的一个。仅在巴尔的摩市，约翰霍普金斯就直接和间接地支持了6万个工作岗位，占该市所有就业岗位的16. 7%。该应用程序将创造或保留2.4个工作岗位。 公共卫生相关性：儿童或成人特发性（原发性）肺动脉高压（IPAH）是一种进行性和致死性疾病，其特征是病因不明的肺动脉压力持续升高。血管扩张剂是治疗的主要药物，然而20-30%的儿童对血管扩张剂没有反应，无反应者的五年生存率为30%。由于病理生物学未知，血管扩张剂治疗具有显著的发病率和成本（约50，000美元/年），并且缺乏血管扩张剂疗效的标志物，我们的长期目标是确定儿童IPAH的血清、诊断和预后标志物，以改善长期结局。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Idiopathic (primary) pulmonary artery hypertension in children or adults (IPAH) is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Vasodilators are the mainstay of therapy, however 20-30% of children do not respond to vasodilators and non- responders have a poor prognosis. As the pathobiology is unknown, vasodilator therapy has significant morbidity and cost (~$50,000/year) and markers of vasodilator therapeutic efficacy are lacking, our long-term goal is to identify serum, diagnostic and prognostic markers of IPAH in children to improve long term outcomes. To pursue this goal, we have optimized an in-depth proteomics approach using abundant protein depletion coupled with intact protein separation methodologies and mass spectrometry to identify even low abundant serum proteins in children with pulmonary hypertension. In our preliminary data using longitudinal serum samples of children with IPAH we have already identified significant changes in a number of serum proteins in response to vasodilator therapy in children with IPAH. Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7 % of all City employment. This application will create or retain 2.4 jobs. PUBLIC HEALTH RELEVANCE: Idiopathic (primary) pulmonary artery hypertension in children or adults (IPAH) is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Vasodilators are the mainstay of therapy, however 20-30% of children do not respond to vasodilators and non-responders have a 30% five year survival. As the pathobiology is unknown, vasodilator therapy has significant morbidity and cost (~$50,000/year) and markers of vasodilator therapeutic efficacy are lacking, our long-term goal is to identify serum, diagnostic and prognostic markers of IPAH in children to improve long term outcomes.