Marlene Rabinovitch
Research Interests
Our research focuses on the regulation of genes associated with cardiovascular development and disease. We identified a novel smooth muscle cell elastase that has a pivotal role in the pathobiology of pulmonary hypertension, vein graft atherosclerosis, transplant arteriopathy and rejection, coronary artery disease, restenosis, myocardial ischemia and myocarditis. Inhibition of elastase prevents or reverses the pathology in experimental animals. We are now pursuing fundamental studies which address the transcriptional regulation of elastase by AML1 and how this relates to genetic mechanisms of disease, focusing on polymorphisms in the serotonin transporter, mutations in a bone morphogenetic protein receptor, and overexpression of a calcium binding protein, Mts1. These studies use cultured cells, transgenic mice, gene arrays and gene therapy and are aimed at developing new treatments.
In our studies related to regulation of cell motility, a key feature of vascular pathology, we identified a requisite increase in production of the microtubule-associated protein LC-3, which is highly conserved across species. This protein regulates the efficiency of mRNA translation of genes, including fibronectin and apolipoprotein D. We determined that LC3, through its triple arginine motif, engages an AU rich element in the 3’ untranslated region of fibronectin mRNA, to enhance efficiency of mRNA translation. We are now addressing whether this process is critical to the regulation of a constellation of transcripts necessary for cell motility in development and disease. We are pursuing evidence that LC3 is regulated by nitric oxide, and are currently investigating how this leads to its phosphorylation and binding to mRNA. In addition, we are relating LC-3 to the migration of other cell types, including neural crest cells which regulate cardiac development, as well as neuronal cells, where it is highly expressed in development, and in diseased tissues and cancer cells. We are utilizing transgenic mice, RNAi, and transcriptional profiling by DNA microarray approaches to investigate the impact of LC3-dependent mRNA translation on cell function.
We have also cloned a novel chymase that mediates enhanced experimental hypertension through processing angiotensin II, endothelin 1, and transforming growth factor beta.
Our research program harmonizes with that of Dr. Richard Bland who investigates the regulation, expression and function of genes that coordinate pulmonary alveolar and vascular development, and how they are perturbed by prematurity and mechanical ventilation, leading to chronic lung disease.
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