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.
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.
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