Cardiac fibrosis is a detrimental side effect of heart disease. The cell population causing this excessive proliferation and deposition of extracellular matrix (ECM) consists primarily of cardiac fibroblasts. Currently treatment strategies for cardiac fibrosis focus solely on the symptoms and not the cause of the fibrosis. Our lab has identified a transcription factor essential to the cardiac fibroblast population: Tcf21. The goal of this proposl is to determine the functional role of Tcf21 in the cardiac fibroblast population. This project has two specific aims, focusing on in vivo and in vitro models.
Our first aim will focus on the cardiovascular phenotype resulting from deletion of Tcf21 in the adult cardiac fibroblast population. Tcf21 is expressed in the resident fibroblast population and that these fibroblasts are active in disease processes. Because Tcf21 is expressed in resting fibroblasts we postulate that it has an essential role in directing gene expression necessary for cardiac fibroblast functions. Loss of Tcf21 will alter cardiac fibroblast normal activities, and we will identify the cellular behaviors resulting from this change in gene expression. Because in vivo analyses will only permit certain studies and some direct versus indirect effects might be difficult to distinguish, i Specific Aim II we will investigate isolated cardiac fibroblasts after manipulation of Tcf21 expression. We will directly test the role of Tcf21 in cellular functions such as proliferation, matrix production, gene expression, and migration. Completion of these specific aims will provide critical knowledge about the role of Tcf21 in the cardiac fibroblast population. These studies will lead to a greater understanding of the cardiac fibroblast and how to best manipulate it at the therapeutic level.
Cardiac fibrosis is a known complication of heart disease and a hallmark of decreased cardiac function. Current treatments focus on the symptoms characteristic of the wall stiffening caused by fibrosis, but do not treat the cells responsible. Te goal of this proposal is to elucidate targets for therapeutics directly targeting cardiac fibroblass.
|Swonger, Jessica M; Liu, Jocelyn S; Ivey, Malina J et al. (2016) Genetic tools for identifying and manipulating fibroblasts in the mouse. Differentiation 92:66-83|