Gene networks beyond organ boundaries; heart, lung and pulmonary vascular disease

描述(由申请人提供)：慢性肺、心脏和血管疾病，如特发性肺纤维化(IPF)、特发性肺动脉高压(IPAH)、继发性肺动脉高压(SPAH)以及左室(LV)和右室(RV)心力衰竭是导致死亡和发病率的重要和常见原因。虽然单个疾病的分子机制已经得到了广泛的研究，但尚不清楚这些分子表型和机制是否跨疾病和器官边界共享。我们的总体目标是利用高通量方法和匹兹堡大学心血管研究所、西蒙斯间质性肺病中心和血管医学研究所丰富的组织资源，识别疾病和器官边界内和疾病范围内的新分子表型。为了确定这些表型，我们将：1.通过分析IPAH或SPAH中失败和非失败的人RV组织；失败和非失败的人LV组织；人IPF和对照肺；IPH和SPAH患者的肺和肺血管；以及来自我们独特的温热尸检计划的相同患者的肺、RV、LV和肺血管来识别组织分子特征。我们将进行mRNA和microRNA表达谱分析，通过高通量qRT PCR验证关键模式和途径，并生成跨器官组织微阵列，以执行高通量组织蛋白验证和定位。2.通过分析LV和RV衰竭患者、IPAH和IPF患者的外周血液，确定在器官和疾病边界内和跨器官和疾病边界容易获得的外周血中疾病存在、阶段和结果的生物标志物。我们将执行mRNA和microRNA表达谱，并确定预测器官和疾病边界内和跨器官和疾病边界的疾病存在、状态和结果的表达模式。3.通过使用先进的计算方法对mRNA和microRNA表达模式以及临床数据进行综合分析，然后通过细胞培养和动物模型验证分析预测，生成与RV和LV衰竭、IPH和IPF的疾病和机制相关的转录图谱。相关性(参见说明)：肺、心脏和血管疾病是经常发生在同一患者身上的常见死亡原因。它们通常被诊断和治疗为不同的实体，但可能具有对相同治疗反应的共同分子机制。我们将利用先进的分子和计算技术，通过分析不同疾病和器官中基因表达的模式来确定这些共同的机制。(摘要结束)

DESCRIPTION (provided by applicant): Chronic lung, heart and vascular diseases such as idiopathic pulmonary fibrosis (IPF), idiopathic pulmonary arterial hypertension (IPAH), secondary pulmonary hypertension (SPAH), and left ventricular (LV) and right ventricular (RV) heart failure are significant and common causes of mortality and morbidity. Although the molecular mechanisms of individual diseases have been extensively studied, it is unknown whether the molecular phenotypes and mechanisms are shared across disease and organ boundaries. Our overall objective is to use high throughput approaches and the extensive resources of well-characterized tissues in the University of Pittsburgh Cardiovascular Institute, the Simmons Center for Interstitial Lung Diseases and the Vascular Medicine Institute to identify new molecular phenotypes across and within disease and organ boundaries. To identify such phenotypes we will: 1. Identify tissue molecular signatures by analyzing failing and non-failing human RV tissue in IPAH or SPAH; failing and non-failing human LV tissue; human IPF and control lungs; lungs and pulmonary vessels of patients with IPAH and SPAH; and lung, RV, LV and pulmonary vessels from the same patients from our unique warm autopsy program. We will perform mRNA and microRNA expression profiling, validate key patterns and pathways by high throughput qRT PCR and generate cross organ tissue microarrays to perform high-throughput tissue protein validation and localization. 2. Identify biomarkers of disease presence, stage and outcome, within and across organ and disease boundaries, in easily accessible peripheral blood by analyzing peripheral blood from patients with LV and RV failure, IPAH and IPF. We will perform mRNA and microRNA expression profiles and determine expression patterns that predict disease presence, state and outcome within and across organ and disease boundaries. 3. Generate a disease and mechanism relevant transcriptional map in RV and LV failure, IPAH and IPF by performing an integrated analysis of mRNA and microRNA expression patterns as well as clinical data with the use of advanced computational approaches, followed by cell culture and animal model validations of analytic predictions. RELEVANCE (See instructions): Lung, heart, and vascular diseases are common causes of death that frequently occur in the same patients. They are usually diagnosed and treated as distinct entities, but may share common molecular mechanisms that respond to the same treatments. We will identify these common mechanisms by analyzing patterns of gene expression in different diseases and organs, using advanced molecular and computational techniques. (End of Abstract)