The genetic basis for primary and secondary pulmonary arterial hypertension (PH) is not known. Recently, mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) have been identified in -50% of cases of familial Primary PH. Only 20% of persons with this BMPR2 mutation, however, develop PH. This strongly suggests that other genetic polymorphisms and environmental factors are necessary to initiate the pathological sequence that leads to expression of the disease. This NRSA grant will utilize inbred rodent strains to help decipher the genetic basis of the development of the disease. A novel consomics approach coupled to extensive gene expression profiling in an established rodent PH model will be utilized to test the hypothesis that modifier genes are involved in the development of severe pulmonary hypertension. Enabled by important preliminary studies involving the drug Sorafenib, a multi-kinase inhibitor model of PH attenuation, we seek to identify candidate genes in this rodent model which will help to better understand the diversity in susceptibility to and development of PH in humans.
Specific Aim #1 will identify a robust menu of Sorafenib-responsive genes in 3 rodent strains that will be exposed to chronic hypoxia and SU5416 (a vascular endothelial growth factor receptor inhibitor), a combination which has been well established as PH- inducing and mimics severe PH in humans.
Specific Aim #2 will narrow this list of novel target genes residing on identified Sorafenib-responsive chromosomes by employing consomic rats containing a single chromosome from a """"""""resistant"""""""" parent strain introgressed into a """"""""sensitive"""""""" strain background. This will allow us to rapidly isolate the chromosome(s) containing genes that influence the development of PH. Comparisons made on the data obtained in these rats will have the power to identify and focus new candidate genes that modify the vascular response to severe PH in humans. Ultimately, knowledge of these modifier genes will empower us to translate the information into novel therapeutic pathways to improve the fatal outcome of the disease and provide the PI an outstanding experience in translational research.
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