一个全新的反义长链非编码RNA HOXA-AS3调控肺血管平滑肌作用网络和分子机制

The proliferation of pulmonary vascular smooth muscle cell(PASMCs) is a major pathological process,leading to pulmonary arterial remodeling and the hypertension(PAH) . long non-coding RNAs are involved in the pathological process.However, the functions and molecular mechanisms of lncRNAs regulating PAH are still largely unknown. We found that HOXA-AS3 expression was upregulated in patients with pulmonary hypertension and experimental animal models. In vitro experiments demonstrated that HOXA-AS3 knockdown significantly inhibited the PASMCs proliferation induced by hypoxia. We hypothesized that HOXA-AS3 promotes the proliferation of PASMCs and the pulmonary vascular remodeling by regulating its sense gene HOXA3 and the interaction between lncRNA and protein.The hypotheses are proved through the following research. Aim 1;Revealing distribution and subcellular localization of HOXA-AS3 and clarifying the role of HOXA-AS3 in proliferation and pulmonary vascular remodeling. Aim 2;Demonstrating HOXA-AS3 formatted a complementary double strand with positive-sense strand RNA of HOXA3 to regulate PASMCs proliferation and molecular mechanism of the regulation; Aim 3: Identifying the specific binding sites and regulatory aspects of HOXA-AS3 and its regulatory proteins. We disclosed for the first time that a antisense lncRNA HOXA-AS3 playing important role in development of PAH. We will clarify the role of HOXA-AS3 signal transduction system and molecular mechanism. We will provide new theoretical and therapeutic targets for revealing the pathogenesis and treatment of PAH.

肺动脉平滑肌细胞（PASMCs）增殖导致肺血管重构是肺动脉高压主要病理过程。长链非编码RNAs（lncRNAs）参与该过程。但参与的lncRNAs及在PASMCs增殖中的作用和机制尚不清楚。我们发现肺动脉高压lncRNA HOXA-AS3表达上调，阻断HOXA-AS3抑制PASMCs增殖。我们假设HOXA-AS3通过调控正义链编码RNA 及通过和蛋白质直接作用促进PASMCs增殖。拟通过HOXA-AS3组织分布、亚细胞定位；HOXA-AS3在增殖中的作用；HOXA-AS3通过与正义链RNA形成互补双链调控PASMCs增殖的机制；HOXA-AS3与与特定功能蛋白结合域，结合位点及调控PASMCs增殖的具体环节等研究证明该假设。本研究将首次探讨HOXA-AS3在肺动脉高压中的作用；阐明HOXA-AS3发挥作用的关键信号分子和作用机制；提供肺动脉高压发病机理和治疗新的理论和靶点。

肺动脉平滑肌细胞增殖过度，肺动脉平滑肌增厚和肺血管管腔狭窄是肺动脉高压的主要原因。长链非编码RNA参与调节血管平滑肌细胞的生物学功能和心血管疾病的病理过程。然而，长链非编码RNA在肺动脉高压的作用在很大程度上仍然是未知的。我们假设一个新的lncRNA，Hoxaas3在肺动脉平滑肌细胞增殖过程中发挥重要的调控作用。通过下述研究证明该假设：1. 缺氧对lncRNA Hoxaas3表达的影响、lncRNA Hoxaas3对细胞增殖和细胞周期分布的影响及在缺氧肺血管重构中的作用；2. LncRNA Hoxaas3调控肺动脉平滑肌细胞增殖的调控网络，关键分子和分子机制；3. 缺氧影响lncRNA Hoxaas3表达的机制。本课题将阐明lncRNA Hoxaas3在肺动脉平滑肌细胞增殖中发挥重要作用，这一发现将有利于促进治疗肺动脉高压的新疗法的发展。