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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Jiang, Xuan; Wooderchak-Donahue, Whitney L; McDonald, Jamie et al. (2018) Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia. Sci Signal 11:
Kashima, Risa; Hata, Akiko (2018) The role of TGF-? superfamily signaling in neurological disorders. Acta Biochim Biophys Sin (Shanghai) 50:106-120
Vattulainen-Collanus, Sanna; Southwood, Mark; Yang, Xu Dong et al. (2018) Bone morphogenetic protein signaling is required for RAD51-mediated maintenance of genome integrity in vascular endothelial cells. Commun Biol 1:149
Kashima, Risa; Redmond, Patrick L; Ghatpande, Prajakta et al. (2017) Hyperactive locomotion in a Drosophila model is a functional readout for the synaptic abnormalities underlying fragile X syndrome. Sci Signal 10:
Kashima, Risa; Roy, Sougata; Ascano, Manuel et al. (2016) Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci Signal 9:ra58
Hata, Akiko; Chen, Ye-Guang (2016) TGF-? Signaling from Receptors to Smads. Cold Spring Harb Perspect Biol 8: