Idiopathic pulmonary fibrosis (IFF) is characterized by fibroblast/myofibroblastic foci and excessive extracellular matrix (ECM) protein accumulation, in which fibroblast migration into the injured areas plays a critical role. Focal Adhesion Kinase (FAK) mediates integrin- and growth factor-initiated cell migration. Overexpression of FAK's C-terminal homologous protein, FAK-related-non-kinase (FRNK), inhibits FAKdependent cell migration promoted by growth factors and integrin receptors in mesenchymal cells. However, the role of FRNK in lung fibroblast migration and its role in tissue injury/repair processes in vivo including lung fibrosis remain undefined. We hypothesize that FRNK modulates lung fibrosis in vivo through inhibition of FAK-dependent fibroblast cell migration. To test this hypothesis, three specific aims are proposed.
In Specific Aim 1, we will determine the role of FRNK in inhibiting FAK-mediated lung fibroblast cell migration and migration signaling. Fibroblast migration will be tested in gain/loss of FRNK function approaches using patient-derived primary human lung fibroblast cells from pulmonary fibrotic patients and non-fibrotic controls.
In Specific Aim 2, we will determine the role of FRNK in lung fibrosis in vivo. The injury/repair response to the pro-fibrotic agent, Bleomycin, will be assessed in FRNK-knockout mice and congenic wild type mice. Furthermore, cell migration and migration signaling of primary lung fibroblasts isolated from these mice will be determined. The role of FRNK in the recruitment, and its resultant fibrotic effects, on bone-marrow derived cells and fibrocytes, and on epitheilal-mesenchymal transition, and on myofibroblast differentiation will be determined.
In Specific Aim 3, we will determine the spatial-temporal relationship of FRNK expression with fibroproliferative lesions in Bleomycin-induced lung fibrosis, and characterize the in vivo mediators of FRNK expression in lung fibroblasts. These data will either support or refute our hypothesis that FRNK modulates fibroblast migration during lung injury and repair, and thereby affects the fibrotic processes in vivo. These studies will support the long-term goal of my laboratory to utilize knowledge gained from these studies to develop novel therapeutic approaches targeted to idiopathic pulmonary fibrosis in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085324-04
Application #
7809480
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2007-05-04
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$362,500
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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