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-ß1 stimulation, 2) Sertad4 protein expression is elevated
in human ischemic heart failure samples, 3) fibroblast Sertad4 expression is induced with TGF- ß 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.