Identification of a novel modulator of Pulmonary Artery Hypertension

 描述(申请人提供)：肺动脉高压(PAH)是一种肺血管疾病，其特征是肺动脉(PAS)的进行性重构，包括PA平滑肌细胞(PASMC)的增殖。PAH是一种不治之症，如果不治疗，会在不到3年的时间内死于右心衰竭。骨形态发生蛋白II型受体(BMPR2)基因杂合性突变是遗传性PAH(HPAH)最常见的遗传原因。然而，只有20%的BMPR2携带者实际发生PAH，这表明在一小部分BMPR2携带者中存在触发PAH发生的额外因素或修饰基因。因此，开发一种预测工具来确定将发生PAH的BMPR2携带者亚群是至关重要的。BMPR2调控因子的发现也有助于阐明HPAH的病因，确定潜在的治疗靶点，并开发一种新的HPAH治疗策略。我们最近发现，BMPR2基因的这个区域介导了FMR1基因产物的RNA结合蛋白FMRP对BMPR2的翻译调控。FMRP的过表达降低了BMPR2蛋白的表达，而FMRP在PASMC中的缺失导致BMPR2的表达及其下游信号反应增加~3倍，包括与CTD相互作用的Lim-kinase1(LIMK1)介导的肌动蛋白重塑。这一应用的中心假设是，FMRP是BMPR2蛋白水平及其下游CTD介导的信号通路的调节因子，因此在BMPR2携带者中起着关键的PAH修饰物的作用。在特定情况下，Aim1将验证FMRP的缺失将通过增强BMPR2蛋白及其下游信号通路来改善PAH的假设。特异性AIM2将验证FMPR水平的变化调节BMPR2-FL转录本的翻译效率并参与PAH发病的假设。特异性Aim3将检验FMRP表达升高影响PAH外显率的假设。在成功完成申请后，它将识别以前未被认识到的“修饰符”，该修饰符在一小部分BMPR2载波中触发PAH的发展。

 DESCRIPTION (provided by applicant): Pulmonary Artery Hypertension (PAH) is a disease of the pulmonary vasculature characterized by progressive remodeling of pulmonary arteries (PAs), including proliferation of PA smooth muscle cells (PASMC). PAH is an incurable disease that leads to death from right ventricular heart failure in less than 3 years if untreated. Heterozygous mutations of the bone morphogenetic protein type II receptor (BMPR2) gene are the most common genetic cause of heritable PAH (HPAH). However, only 20% of BMPR2 carriers actually develop PAH, indicating an existence of additional factors or modifier genes that trigger the development of PAH in a small subset of BMPR2 carriers. Therefore, it is critical to develop a prognostic tool to identify the subset of BMPR2 carriers who will develop PAH. The discovery of a BMPR2 modulating factor can also help clarify the etiology of HPAH, identify potential therapeutic targets, and develop a novel therapeutic strategy for HPAH. We found recently that the region of the BMPR2 mRNA mediates the translational regulation of BMPR2 by the RNA binding protein FMRP (fragile X mental retardation protein), a product of the FMR1 gene. Overexpression of FMRP reduces BMPR2 protein, while deletion of FMRP in PASMC results in a ~3-fold increase of both BMPR2 expression and of its downstream signal response, including actin remodeling mediated by LIM-kinase 1 (LIMK1), which interacts with the CTD. The central hypothesis of this application is that FMRP is a regulator of BMPR2 protein level and its downstream CTD- mediated signaling pathway, and, therefore, serves as a critical modifier of PAH among BMPR2 carriers. In Specific Aim1 will test the hypothesis that the depletion of FMRP will ameliorate PAH by augmenting BMPR2 protein and its downstream signaling pathway. Specific Aim2 will test the hypothesis that the change of the level of FMPR modulates the translation efficiency of BMPR2-FL transcripts and contributes to the pathogenesis of PAH. Specific Aim3 will test the hypothesis that the elevated expression of FMRP affects the penetrance of PAH. Upon successfully completion of the application, it will identify a previously unappreciated "modifier" which triggers the development of PAH among a small subset of BMPR2 carriers.