The long term goal of the research is to elucidate the cellular and molecular basis of excess scar formation during wound repair. Keloids are tumor-like skin scars that affect 10 to 20% of people of African decent, Asians, and Hispanics without appropriate treatments. During the past funding period, we used 14 freshly isolated and low passages (<3) strains of normal and keloid fibroblasts from human patients and provided new evidence that (PAI-1) overexpression and elevated collagen accumulation are intrinsic features of keloid fibroblasts. We also provided new and different evidence of a causal relationship between PAI-1 expression and collagen accumulation: adenoviral overexpression and siRNA and shRNAmir suppression demonstrate that PAI-1 produces elevated collagen accumulation in normal and keloid fibroblasts, respectively. Finally, by testing protease-inhibitory and vitronectin-binding mutants of PAI-1 for their capacity to induce collagen accumulation, we found that the latter was equipotent with wild-type PAI-1 and the former was only ~50% effective. Thus, PAI-1 utilizes protease inhibition as well as another of its functions to control collagen accumulation (Tuan et al., 2008, Am J Pathol). The goals of the renewal application are 1) to advance a therapeutic strategy that targets plasminogen activator inhibitor-1 (PAI-1) to control keloid collagen accumulation and prevent or treat keloid formation;2) to further define and expand the mechanisms utilized by PAI-1 to regulate collagen accumulation in keloid fibroblasts.

Public Health Relevance

The long term goal of the research is to elucidate the cellular and molecular basis of excess scar formation during wound repair. The goals of the renewal application are to advance two potential therapeutic strategies in targeting plasminogen activator inhibitor- 1 to control keloid collagen accumulation based on our laboratory findings using freshly isolated/early passages of human patient cells, and to further the mechanism underlying PAI-1-dependent and -independent regulation of keloid collagen accumulation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-E (02))
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Hagan, Ann A
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Children's Hospital of Los Angeles
Los Angeles
United States
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Lien, Ching-Ling; Harrison, Michael R; Tuan, Tai-Lan et al. (2012) Heart repair and regeneration: recent insights from zebrafish studies. Wound Repair Regen 20:638-46
Kim, Jieun; Rubin, Nicole; Huang, Ying et al. (2012) In vitro culture of epicardial cells from adult zebrafish heart on a fibrin matrix. Nat Protoc 7:247-55
Lee, Yun-Shain; Wysocki, Annette; Warburton, David et al. (2012) Wound healing in development. Birth Defects Res C Embryo Today 96:213-22
Kim, Jieun; Wu, Qiong; Zhang, Yolanda et al. (2010) PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts. Proc Natl Acad Sci U S A 107:17206-10
Yeh, Jennifer; Green, Lydia M; Jiang, Ting-Xin et al. (2009) Accelerated closure of skin wounds in mice deficient in the homeobox gene Msx2. Wound Repair Regen 17:639-48
Dudas, Marek; Wysocki, Annette; Gelpi, Brian et al. (2008) Memory encoded throughout our bodies: molecular and cellular basis of tissue regeneration. Pediatr Res 63:502-12
Tuan, Tai-Lan; Hwu, Paul; Ho, Wendy et al. (2008) Adenoviral overexpression and small interfering RNA suppression demonstrate that plasminogen activator inhibitor-1 produces elevated collagen accumulation in normal and keloid fibroblasts. Am J Pathol 173:1311-25
Li, Wai-Yee; Huang, Eunice Y; Dudas, Marek et al. (2006) Transforming growth factor-beta3 affects plasminogen activator inhibitor-1 expression in fetal mice and modulates fibroblast-mediated collagen gel contraction. Wound Repair Regen 14:516-25
Huang, Eunice Y; Wu, Huayang; Island, Eddie R et al. (2002) Differential expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in early and late gestational mouse skin and skin wounds. Wound Repair Regen 10:387-96
Island, E; Wu, H; Warburton, D et al. (1999) Developmental differences in the expression and modulation of extracellular matrix proteases and inhibitors in mouse skin fibroblasts. Wound Repair Regen 7:467-76