Pulmonary hypertension (PH) is a disorder of the lung vasculature defined by increased mean pulmonary arterial pressure (mPAP) leading to right ventricle (RV) hypertrophy and dysfunction, right-sided heart failure and ultimately death. The pathologic process in PH is characterized by extensive vascular remodeling affecting pulmonary artery smooth muscle cells (PASMC) and the RV wall. Several process have been associated with the development of pulmonary hypertension including increased perivascular fibro-proliferative deposition altered cellular metabolism and increased cell proliferation and resistance to apoptosis. Recent advances in the field of RNA biology have shown that alternative polyadenylation (APA) results in shorter 3'-untranslated regions (3'UTR) of mRNAs that can avoid mRNA regulation resulting in overexpression of these transcripts. Recent studies have shown that 3'UTR is present following cellular stress. Depletion of a 25kDa subunit of the RNA binding protein cleavage factor I (CFIm25), has been shown to result in APA and marked 3'UTR shortening. Provocative preliminary data from my lab demonstrate depletion of CFIm25 and evidence of 3'UTR shortening from isolated pulmonary arteries from models of pulmonary hypertension. These observations are in line with evidence of 3'UTR shortening in isolated pulmonary artery smooth muscle cells. However, the effects of 3'UTR shortening in PH remain unknown. Pathway analysis from CFIm25 knock-down studies in PASMCs revealed 3'UTR shortening of genes associated with fibro-proliferative deposition and cellular proliferation. Taken together, our hypothesis is that 3'UTR shortening alters gene expression of many factors influencing the development of PH.
Aim 1 will address how temporal changes in CFIm25 depletion lead to increased vascular remodeling through 3'UTR shortening. We will also evaluate expression levels of CFIm25 using patient-derived tissues and PASMCs to track how depletion of CFIm25 correlates with disease severity in PH. Using novel RNA- seq approaches in murine and human tissue we aim to identify changes in 3'UTR length in pathways contributing to the development of PH.
In Aim 2, we will evaluate how CFIm25 depletion in vascular smooth muscle cells worsens the development of PH. Here we will also perform novel RNA-seq approaches to identify shortened 3'UTRs following depletion of CFIm25.
Aim 3 will determine the levels of miRs-203 and miR-509-3p in patients with PH and in experimental models of PH. We will test the therapeutic potential of strategies aimed at elevating CFIm25 expression as a novel treatment for PH.
Pulmonary hypertension is a disorder of the pulmonary vasculature defined by increased mean pulmonary arterial pressure (mPAP) leading to right-sided heart failure and ultimately death with 3 to 5 years of diagnosis; it can appear on its own or in association with chronic lung diseases. This proposal examines the mechanisms by which a process known as Alternative Polyadenylation leads to 3'UTR shortening contributing to vascular remodeling in PH. Knowledge obtained from these studies could lead to novel therapeutic options for patients suffering from pulmonary hypertension.
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