Although many genes have been implicated in the pathogenesis of PAH, PAH is such a complex disease that there are probably multiple genes involved. It is possible that these genes are under the influence of key regulatory mechanisms. MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules consisting of approximately 21-25 nt. miRNAs recognize their targets through complementary sequences in their 3'-untranslated regions (UTR) of their mRNA and form RNA-induced silencing complexes, leading to the partial degradation of mature mRNA or translation repression. miRNA pathways are evolutionarily conserved and regulate many aspects of cell functions including cell cycle, differentiation, proliferation, survival, and metabolism. Single miRNAs can regulate up to hundreds of genes or proteins, making them attractive targets for study in the pathogenesis of PAH. In this proposal, we propose three interrelated aims:
Aim 1 is to determine and validate changes in miRNA expression in pulmonary arterial smooth muscle (PASMC) cells and lung tissue from PAH and control subjects;
Aim 2 is to determine whether miR-143 is downregulated and the expression of its targets is altered in PASMC and lung tissues of PAH patients;
and Aim 3 is to determine whether miR-17~92 cluster is downregulated and their targets are upregulated in PASMC and lung tissue of PAH patients.
Pulmonary hypertension in humans is a devastating disease and there is no cure. A better understanding of the mechanisms involved should help us get to improved treatment and prevention of this disease. Micro RNAs are small molecules that control the expression of several genes. By studying the expression of these microRNAs in diseased and control human lungs, we hope to identify key microRNAs that are involved in the pathogenesis of pulmonary hypertension in humans. Completion of the proposed studies will provide novel insights into the pathophysiology of PAH, which may result in the design of novel strategies for the treatment of patients with this disease.
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