Thursday, December 26, 2024
12/26/2024
Abstract Heart failure is a progressive disease that is often exacerbated by inappropriate cardiac remodeling in response to stress. However, therapies that can efficiently target fibrosis, a key component of pathologic remodeling, are currently unavailable. While an inflammatory response after acute injury is essential for clearing dead tissue, and some fibrosis may be necessary to maintain the tensile strength of injured myocardium, a sustained inflammatory response can lead to inappropriate amounts of fibrosis. Several resident cardiac cell populations have been implicated in regulating the composition and activation of immune cells after acute heart injury, but the role of cardiac fibroblasts in this process is poorly understood. The goal of these studies is to elucidate the role that fibroblasts play in regulating inflammation. Our preliminary data demonstrate that initial innate immune responses proceed normally in the absence of fibroblasts, but populations of inflammatory cells persist longer than when in the presence of fibroblasts. We hypothesize that Ras signaling in cardiac fibroblasts directs anti-inflammatory gene expression later in the remodeling process and identification of these pathways will permit the differentiation of pathogenic and regenerative remodeling. In Aim I, we will use cardiac fibroblast ablation to identify the timing of anti-inflammatory signals. We will then determine the specific anti-inflammatory regulators. In Aim II, we will manipulate Ras signaling in fibroblasts to determine how alteration of this pathway controls inflammatory cell infiltration, activation, and subsequent remodeling. In Aim III, we will determine if these inflammatory regulators are conserved in human cardiac fibroblasts. This project will provide novel insights into the role that cardiac fibroblasts play in immune regulation after cardiac injury, and identify signaling pathways that may be therapeutically modulated to limit pathologic remodeling.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).