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室衰竭为特征的致死性综合征。虽然根本原因仍然难以捉摸，但许多诱发和疾病修饰异常在肺血管系统和右心中产生癌样、增殖性、抗凋亡表型。近年来，国内外研究表明，代谢信号通路的破坏（如线粒体异常）有助于PAH的发病机制，并成为有前景的治疗靶点。表观遗传调节在肺血管疾病（包括PAH）的表现中起着重要作用，这一点也越来越清楚。最近出现的技术，以检查控制的转录，包括表观遗传修饰在全基因组水平。鉴于RFA提供的独特机会，本探索性研究的目标是从整个表观基因组中识别有助于PAH发病机制的全基因组甲基化（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风险改变相关; 2）代谢信号传导（如线粒体异常）的破坏是PAH的统一原因。为了验证这一假设，我们打算（1）使用Illumina Methyl 450 K分析，比较IPAH病例和非疾病对照中来自人类基因组中> 450，000个甲基化位点的GWM谱，并比较从肺组织和外周血获得的GWM谱，以验证血液来源DNA作为替代组织;（2）定义表观遗传途径对基因表达的全局调节的贡献;和（3）使用PAH患者的血清和肺组织样品验证来自GWM谱和基因表达谱的靶标，包括作为生物标志物的代谢信号传导途径分子。如果成功，我们提出的研究将提供对表观遗传靶向的机制见解，并可用于开发逆转特定致病、异常表观遗传变化的工具，作为PAH的潜在新型治疗方法。

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.