Identification of a novel modulator of Pulmonary Artery Hypertension

 描述（由申请方提供）：肺动脉高压（PAH）是一种肺血管系统疾病，其特征为肺动脉（PA）进行性重塑，包括PA平滑肌细胞（PASMC）增殖。PAH是一种无法治愈的疾病，如果不治疗，会在不到3年的时间内导致右心室心力衰竭死亡。骨形态发生蛋白II型受体（BMPR 2）基因的杂合突变是遗传性PAH（HPAH）最常见的遗传原因。然而，只有20%的BMPR 2携带者实际上发展为PAH，这表明在一小部分BMPR 2携带者中存在触发PAH发展的额外因素或修饰基因。因此，开发一种预后工具来识别将发展为PAH的BMPR 2携带者子集至关重要。BMPR 2调节因子的发现也有助于阐明HPAH的病因，确定潜在的治疗靶点，并为HPAH开发新的治疗策略。我们最近发现，BMPR 2 mRNA的区域介导的RNA结合蛋白FMRP（脆性X智力低下蛋白），FMR 1基因的产物的BMPR 2的翻译调节。FMRP的过表达减少了BMPR 2蛋白，而PASMC中FMRP的缺失导致BMPR 2表达及其下游信号应答增加约3倍，包括由与CTD相互作用的LIM激酶1（LIMK 1）介导的肌动蛋白重塑。本申请的中心假设是FMRP是BMPR 2蛋白水平及其下游CTD介导的信号传导途径的调节剂，因此在BMPR 2携带者中充当PAH的关键修饰剂。在特定的Aim 1将测试的假设，即FMRP的消耗将改善PAH通过增加BMPR 2蛋白及其下游信号通路。特异性Aim 2将验证FMPR水平的变化调节BMPR 2-FL转录本的翻译效率并有助于PAH发病的假设。特异性Aim 3将检验FMRP表达升高影响PAH发病率的假设。在成功完成申请后，它将识别出一种以前未被认识到的“修饰剂”，该修饰剂在一小部分BMPR 2携带者中触发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.