Lumican (Lum) belongs to the small leucine rich proteoglycan family and is a constituent of the extracellular matrix and serves as a matrikine (a term pertaining to ECM components and their proteolytic peptides that are able to regulate cell activity). Lum contributes to corneal transparency and is essential for corneal wound healing, but little is known regarding how this is achieved. Our recent findings suggest that TGF? type I receptor (TGFBR1/ALK5) is a novel Lum receptor.
We aim to examine the biological significance of Lum/ALK5 interaction accounting for the pleiotropic function of Lum and TGF? signaling in regulating various cellular responses during embryonic development and pathogenesis. Lumican binds ALK5 and promotes wound healing of HTCE (human telomerase-immortalized corneal epithelial) cells by alleviating the suppression of cell proliferation and up-regulating EGFR-ligands to sustain ERK activation.
Specific Aim 1 will examine the mechanism responsible for the enhanced in vitro wound healing elicited by the Lum/ALK5 complex. This will be achieved by examining the fate of TGFBR polymers following Lum binding to ALK5, by assessing the role of epiregulin up-regulation and through the identification of the ALK5 domain(s) required for interacting with Lum and or Src.
Specific Aim 2 will examine the in vivo mechanism by which Lum/ALK5 promotes wound healing. This will be achieved through the use of various transgenic mouse models to examine the hypothesis that the ALK5/TGFBR2 polymer is required for Lum binding and subsequent promotion of wound healing. In addition this aim, will further examine the ALK5 intracellular domain that may mediate wound healing. Finally Specific Aim 3 will set out to identify and characterize therapeutic LumC peptides for wound healing, specifically the compromised wound healing seen in diabetic patients. The completion of the proposed studies will not only expand our understanding beyond the current central dogma of signaling cascades elicited by TGF?, but will also identify and characterize therapeutic peptides for treating persistent epithelium defects.

Public Health Relevance

Lumican (Lum), a keratan sulfate proteoglycan in corneal stroma, belongs to the small leucine rich proteoglycans (SLRPs) family. Lumican has multiple matricellular functions, serves as a component of extra cellular matrix for the formation and maintenances of transparent cornea and is a matrikine regulating cellular activities in normal and disease. Lumican binds to ALK5 to promote wound healing. LumC13 the last C-terminal 13 amino acids of lumican and its derivative LumC13C-A can promotes corneal wound healing of normal and diabetic mice same as full length lumican molecule. Elucidation of the molecular and cellular mechanism will yield useful information on how this proteoglycan participates in maintenance of tissue homeostasis. The identification and characterization of Lum peptides will lead to the development of therapeutic peptides for promoting wound healing.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY011845-10A1
Application #
8774021
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
1999-04-01
Project End
2018-06-30
Budget Start
2014-09-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
$546,015
Indirect Cost
$201,526
Name
University of Cincinnati
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Coulson-Thomas, Vivien J; Coulson-Thomas, Yvette M; Gesteira, Tarsis F et al. (2016) Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System. Ocul Surf 14:121-34
Castillo, Eliseo F; Zheng, Handong; Van Cabanlong, Christian et al. (2016) Lumican negatively controls the pathogenicity of murine encephalitic TH17 cells. Eur J Immunol 46:2852-2861
Kao, Winston W-Y; Coulson-Thomas, Vivien J (2016) Cell Therapy of Corneal Diseases. Cornea 35 Suppl 1:S9-S19
Coulson-Thomas, Vivien Jane; Chang, Shao-Hsuan; Yeh, Lung-Kun et al. (2015) Loss of corneal epithelial heparan sulfate leads to corneal degeneration and impaired wound healing. Invest Ophthalmol Vis Sci 56:3004-14
Dong, Fei; Liu, Chia-Yang; Yuan, Yong et al. (2015) Perturbed meibomian gland and tarsal plate morphogenesis by excess TGFα in eyelid stroma. Dev Biol 406:147-57
Coulson-Thomas, Vivien Jane; Gesteira, Tarsis Ferreira; Esko, Jeffrey et al. (2014) Heparan sulfate regulates hair follicle and sebaceous gland morphogenesis and homeostasis. J Biol Chem 289:25211-26
Kao, Winston W-Y; Liu, Hongshan; Zhang, Jianhua (2013) Wakayama symposium: challenges of future research in ocular surface cell biology. Ocul Surf 11:19-24
Coulson-Thomas, Vivien J; Coulson-Thomas, Yvette M; Gesteira, Tarsis F et al. (2013) Lumican expression, localization and antitumor activity in prostate cancer. Exp Cell Res 319:967-81
Yamanaka, Osamu; Yuan, Yong; Coulson-Thomas, Vivien Jane et al. (2013) Lumican binds ALK5 to promote epithelium wound healing. PLoS One 8:e82730
Liu, Hongshan; Zhang, Jianhua; Liu, Chia-Yang et al. (2012) Bone marrow mesenchymal stem cells can differentiate and assume corneal keratocyte phenotype. J Cell Mol Med 16:1114-24

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