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.
Heterozygous germline mutations in the BMPR2 gene are known to cause pulmonary artery hypertension (PAH), however, only 20% of BMPR2 carriers actually develop PAH, supporting the idea that there is a 'modifier' which determines the development of PAH among a subset of BMPR2 carriers. This application studies a novel modifier which triggers the development of PAH among a small subset of BMPR2 carriers.
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