Arya Mani

My laboratory is engaged in system biology approaches to investigate cardiovascular diseases. We leverage modern techniques of functional genomics, epigenetics, transcriptomics, proteomics, gene editing and model-driven experimentation to understand the underlying causes of atherosclerosis and metabolic syndrome and discover therapeutic targets. Our work involves population and family-based genetic studies, high throughput sequencing to identify disease genes, with a focus on coronary artery disease (CAD) and metabolic syndrome (MetS). We then proceed to characterize the identified genes in vivo and in vitro. By recruiting more than thousand kindreds with early onset CAD and multiple metabolic risk factors for genetics and metabolic studies we have been able to map, identify and characterize a dozen of human disease genes for CAD and MetS, which have been reported in leading journals such as Nat Genet, Science, NEJM, Cell Metab, JCI, PNAS, AJHG, etc. We were the first group to show the role of Wnt signaling in atherosclerosis and the first to establish a genetic link between exocrine and endocrine pancreas in pathogenesis of diabetes. Most recently, we have established techniques of high throughput gene editing and multiple parallel reporter assays in my laboratory and have successfully mapped the regulatory landscape of a number of GWAS disease genes. Subsequent molecular and physiological studies in human mutation carriers and animal models have allowed us to unravel novel functions of the identified genes, to delineate their cognate pathways and to discover new targets for pharmaceutical intervention. These groundbreaking achievements have made us one of the leading laboratories in investigation of metabolic syndrome. We have developed expertise in in vivo investigation of lipid and glucose metabolism, insulin secretion and sensitivity, and vascular biology and in human physiological studies, leading to discovery of attractive drug targets that have been either patented or being investigated for their utility in treatment of fatty liver disease and diabetes in 2 clinical trials in the outlier populations of Fars/Iran. One of our groundbreaking discoveries was the identification of founder mutations in the DYRK1B gene, underlying atherosclerosis, metabolic syndrome, and fatty liver disease. The encoded protein is upregulated in human steatosis (NASH). Our studies in mice have shown that this upregulation results in mTOR activation, lipogenesis and development of NASH and dyslipidemia. Strikingly, knockdown of Dyrk1b is protective against these traits, motivating further investigations to characterize the protein as an attractive therapeutic target. One of our recent groundbreaking discoveries was the identification of novel loss of function mutations in a gene encoding the pancreatic exocrine elastase Cela2a in patients with diabetes, CAD and MetS traits, including obesity, hypertension, hypertriglyceridemia, NAFLD (OMIM: AOMS4). The characterization of this protein in vivo has shown that it widely expressed in different tissues and circulates in the blood, its levels rise after food intake in humans and stimulates insulin secretion and sensitivity and inhibits platelet aggregation. We are now fully characterizing this protein and evaluating its utility as a drug target for diabetes, dyslipidemia, and fatty liver disease. These discoveries are the results of lengthy and high risk studies, which would have not been accomplished without the R35 grant mechanism and the hard work and devotion of students, residents , fellows and visiting scholars in my laboratory, many of whom have gone to establish their own labs, or join the industry. Alone 7 former lab members have joined academia over the past 5 years and 11 a pursuing a career in research as trainees.