Cardiac fibrosis is a major component of heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that attenuate fibrosis directly. This major hurdle can be overcome by targeting the resident fibroblast. Our preliminary data indicate that PDGFRa signaling is necessary for the maintenance of the resident cardiac fibroblast. The objective of this study is to determine the role of both the fibroblast and PDGFRa signaling in cardiac fibrobrosis at baseline and after myocardial infarction. This proposal has 2 aims: First, we will define the role of PDGFRa in fibroblast maintenance by specifically removing PDGFRa expression in cardiac fibroblasts and determining the survival and proliferation of these cells in vivo. To further elucidate the mechanism of fibroblast loss in the absence of PDGFRa signaling we will determine the cellular function causing this disruption and examine signaling pathways that control this function. This information could identify mechanisms for controlling cardiac fibroblast numbers.
Our second aim i s to examine the role of fibroblasts during normal heart function and after injury. We will focus extracellular matrix deposition, cardiomyocyte and vascular alterations before injury. We will then determine how loss of fibroblasts affects the response of the heart to injury using heart function, area of fibrosis, and cardiomyocyte hypertrophy as hallmarks. Completion of these studies will provide a greater understanding of the fibroblast and the progression of fibrosis with regards to PDGFRa signaling.

Public Health Relevance

Cardiac fibrosis is the process of wall stiffening during heart disease and is a hallmark of decreased cardiac function. Currently, there are no treatments that directly and specifically target the fibroblast responsible for the fibrosis. The goal of this propsal is to investigate a signaling pathway that is required for this cell population to survive and to study how heart function is affected by loss of these cells.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Meadows, Tawanna
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University of Hawaii
Internal Medicine/Medicine
Schools of Medicine
United States
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Ivey, Malina J; Kuwabara, Jill T; Pai, Jonathan T et al. (2018) Resident fibroblast expansion during cardiac growth and remodeling. J Mol Cell Cardiol 114:161-174
Kanisicak, Onur; Khalil, Hadi; Ivey, Malina J et al. (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat Commun 7:12260
Pinto, Alexander R; Ilinykh, Alexei; Ivey, Malina J et al. (2016) Revisiting Cardiac Cellular Composition. Circ Res 118:400-9
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
Ivey, Malina J; Tallquist, Michelle D (2016) Defining the Cardiac Fibroblast. Circ J 80:2269-2276