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.

Public Health Relevance

Fibrosis, often associated with organ damage and inflammation, is a key step in heart failure. The cells responsible are fibroblasts, and we require more information regarding their importance in regulation of inflammation. It is thought that these cells have both beneficial and deleterious actions. The goal of this proposal is to identify how fibroblasts interact with inflammatory cells after cardiac injury and to learn how differences in signaling impact long term scar formation. The outcomes of this study will help to determine potential drug targets for therapeutic intervention as well as identify the optimal time frame for this intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL144067-03
Application #
9963042
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2018-08-11
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822