Investigation of MiR-140-5p in Humans and Experimental Models of Pulmonary Arterial Hypertension.

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Pulmonary Arterial Hypertension:Pulmonary arterial hypertension (PAH) is a devastating and debilitating disease affecting 5 people per million. It is caused by narrowing of the arteries of the lungs and leads to high blood pressure in the lungs and failure of the heart. Severe shortness of breath, heart failure and death are common among sufferers despite recent advances in scientific understanding and clinical treatment of the disease.What Causes Pulmonary Arterial Hypertension?The causes of PAH are incompletely understood. Specific gene mutations are common within families with PAH. This finding had lead to the identification of cellular pathways important in causing PAH. Mutations of BMPR2, a cell surface receptor protein, reduce signalling in the BMPR2 pathway and cause PAH; however, not all patients with mutations of BMPR2 develop the disease. Mutations in other genes leading to reduced BMPR2 signalling can cause PAH and reduced BMPR2 signalling is seen in several experimental models of PAH. These observations have lead to the 'multiple hit' model of pathology in which several genetic 'hits' each reduce BMPR2 signalling and together cause PAH.What are microRNA?MicroRNA are short RNAs that alter the expression of genes within the cell by specifically targeting and preventing the production of proteins. Blood microRNA expression levels have been used as markers of disease in cancer and heart disease. Manipulation of microRNA levels is also used experimentally to treat several diseases. The first human trial of a microRNA based drugs are being undertaken currently.New Findings and Opportunities:The Pulmonary Vascular Research Group in Sheffield has extensive experience in PAH research with expertise in cell culture and experimental models of PAH. The Sheffield Pulmonary Vascular Unit is one of five national centers for clinical investigation of PAH. Prospective collection from patients with newly diagnosed pulmonary hypertension referred to the Sheffield Pulmonary Vascular Unit has created an extensive biobank of blood samples with associated clinical data from over 300 patients.New results from our lab show that patients with PAH have altered microRNA expression patterns in their blood. Further experiments show that reproducing these microRNA changes in human lung artery cells alters the levels of proteins known to regulate BMPR2 signalling. These changes act in a way that would reduce BMPR2 signalling in the manner seen in PAH.Hypotheses:1 Reduced levels of specific microRNA are an important change leading to PAH2 Blood microRNA expression levels may be used as a marker of PAHAims:The aim is to complete our study of microRNA expression in blood samples taken from PAH, examine the effects of altered microRNA expression in human lung cells and test these microRNA as a potential treatment in experimental models of PAH.Experiments:We aim to test our hypothesis by manipulating microRNA levels in human lung artery cells. To determine the effect of the changes in microRNA levels we will asses levels of mRNA and protein of targets within the cell and examine cell growth and movement of cells as indicators of cell function. We will examine expression levels of microRNA expression in experimental models of PAH. Finally we will test a microRNA drug to determine if the changes prevent and treat PAH in experimental models.Conclusion:New findings suggest an exciting link between blood microRNA changes and the mechanisms causing PAH. The Sheffield Pulmonary Vascular Unit blood sample collection provides a unique opportunity to investigate blood microRNAs a biomarker for PAH and the expertise of the Pulmonary Vascular Research Group provide an opportunity to investigate how the observed microRNA changes affect experimental models of PAH.