A Genome-wide Methylation Study of Epigenetic Contributions to PAH

描述：肺动脉高压是一种以血管阻塞和右心衰竭为特征的致命性综合征。虽然根本原因仍不清楚，但许多诱因和疾病改进性异常会在肺血管和右心产生一种癌样、增殖、抗凋亡的表型。最近，来自他人和我们自己的研究表明，代谢信号通路的破坏，如线粒体异常，参与了PAH的发病机制，并成为有希望的治疗靶点。表观遗传调控在包括PAH在内的肺血管疾病的表现中起着重要作用。最近出现了检查转录控制的技术，包括全基因组水平的表观遗传修饰。鉴于这种RFA提供了独特的机会，这项探索性研究的目标是从整个表观基因组中识别有助于PAH发病的全基因组甲基化(GWM)谱。我们假设：1)GWM谱中的表观遗传修饰在基因表达调控中起主要作用，并与PAH的风险改变有关；2)代谢信号的中断，如线粒体异常，是PAH的统一原因。为了验证这一假设，我们打算(1)使用Illumina甲基450K分析，比较来自人类基因组中450,000个甲基化位点的IPAH患者和非疾病对照的GWM谱，并比较从肺组织和外周血获得的GWM谱，以验证血源DNA作为替代组织的有效性；(2)确定表观遗传途径对基因表达的全球调控的贡献；以及(3)使用PAH患者的血清和肺组织样本，验证GWM谱和基因表达谱(包括代谢信号通路分子)作为生物标记物的靶点。如果成功，我们提议的研究将为表观遗传学靶向提供机械性见解，并可用于开发工具来逆转特定致病、异常表观遗传学变化，作为治疗PAH的潜在新方法。

DESCRIPTION: Pulmonary arterial hypertension is a lethal syndrome characterized by vascular obstruction and right ventricular failure. Although the fundamental cause remains elusive, many predisposing and disease-modifying abnormalities create a cancerlike, proliferative, apoptosis-resistant phenotype in pulmonary vasculature and the right heart. Recently studies from others and our own suggested that disruption of the metabolic signaling pathway such as mitochondrial abnormalities contribute to the pathogenesis of PAH and constitute promising therapeutic targets. It is also becoming clear that epigenetic regulation plays an important role in the manifestation of lung vascular disease including PAH. Recently technologies have emerged to examine the control of transcription including epigenetic modifications at genome-wide level. Given the unique opportunity this RFA provides, the goal of this exploratory study is to identify genome-wide methylation (GWM) profiles from across the epigenome that contribute to PAH pathogenesis. We hypothesize that 1) epigenetic modification in GWM profiles plays a major role in the regulation of gene expression and is associated with altered risk of PAH and 2) disruption of metabolic signaling such as mitochondrial abnormalities represents the unifying cause for PAH. To test this hypothesis, we intend to (1) compare GWM profiles in IPAH cases and non-disease controls from >450,000 methylation sites in the human genome, using the Illumina Methyl450K analysis, and compare GWM profiles obtained from lung tissue and peripheral blood to validate blood-source DNA as surrogate tissue; (2) define the contribution of epigenetic pathways to the global regulation of gene expression; and (3) validate targets from GWM profiles and gene expression profiling including metabolic signaling pathway molecules as biomarkers using serum and lung tissue samples from patients with PAH. If successful, our proposed research will provide mechanistic insights into epigenetic targeting and can be used to develop tools to reverse specific disease-causing, aberrant epigenetic changes as a potential novel therapeutic approach for PAH.