Clinical Phenotyping and Disease Specific Sampling to Identify Non-coding RNAs for Human Therapeutics in PAD

Project Narrative – Public Health Relevance Peripheral arterial disease (PAD) is a major health problem that afflicts millions of patient in the United States. PAD is caused by atherosclerosis where blockages impair blood flow to the legs. PAD is crippling disease and there are no medical therapies that have the ability to improve blood flow to the legs of patients suffering from PAD. The central dogma of molecular biology states that DNA makes RNA and RNA makes protein. Yet, the vast majority of mammalian DNA does not encode any gene or genes. These regions are collectively call, non-coding RNAs which include both micro-RNAs and long non-coding RNAs. These molecules are now recognized as powerful factors that regulate the response to injury and thus are an important area for investigation. In general genes that encode proteins are well conserved along evolution but this is not the case for non-coding RNAs; thus the study of human material is critical for the study and plan. Non-coding RNAs carry out diverse functions without being translated into proteins. We will identify micro-RNA and lncRNAs that are altered in ischemic muscle and in peripheral blood of patients with peripheral arterial disease (PAD) to determine how they contribute to the disease phenotype and whether they can be developed into biomarker for diagnosis of PAD. This project will identify the mechanisms of action of these new regulators of disease and open the door for future therapeutic strategies that use or manipulate the non-coding RNAs for treatment of PAD.