The role of Sertad4 in pathologic cardiac remodeling.

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Heart failure is a major public health problem, affecting over 6 million Americans with a 5 year mortality rate over 40%. Heart failure has been “cured” many times in rodents, yet remains a leading cause of death in humans. This is in part, because many of the strategies so effective in rodent models, target molecules and processes that are essential for baseline physiology. Upon more rigorous testing in pre-clinical development, these strategies are proven unsafe and fail to progress into the clinic. This project uses an essential gene, BRD4, as a molecular flashlight to identify new targets that are specifically activated in pathologic conditions. The proposal will test a thus far unstudied nuclear protein, Sertad4, for its role in activating and sustaining pathologic gene expression programs in the cardiac fibroblast. Sertad4 is expressed in far fewer cell-types than many recently investigated targets that have generated considerable enthusiasm, including BRD4 (expressed in all cells). It is our hope that targeting proteins with more selective expression profiles will limit collateral damage of potential therapeutics, though no interventions are true silver bullets. Ultimately, the proposal will establish if in vivo inhibition of Sertad4 prevents fibroblast activation and preserves cardiac function following myocardial infarction. As an assistant professor, Dr. Stratton has assembled a supporting team of co-investigators and collaborators to help robustly test this hypothesis. Support for the hypothesis is found in substantial preliminary data showing that: 1) Sertad4 is essential for fibroblast activation (proliferation and myofibroblast differentiation) in response to TGF-β1 stimulation, 2) Sertad4 protein expression is elevated in human ischemic heart failure samples, 3) fibroblast Sertad4 expression is induced with TGF- β 1 stimulation in a BRD4 and p38 dependent manner (BRD4/p38 are also necessary for fibroblast activation), 4) Sertad4 is robustly expressed at sites of interstitial and perivascular cardiac fibrosis, and 5) targeting Sertad4 reduces SMAD2/3 protein expression and SMAD2/3 target gene expression. Innovative and cutting edge approaches are proposed to define how Sertad4 causes fibroblast activation, and determine if manipulating Sertad4 expression in vivo alters the course of pathologic remodeling following myocardial infarction. This project will rigorously test the ability to target Sertad4 to prevent cardiac fibrosis and heart failure, while also establishing fundamental knowledge regarding the molecular mechanisms of this novel target.