Structure/Function Relationship of the Lumican Gene

描述(由申请人提供)：Lumcan(Lum)属于富含亮氨酸的小蛋白多糖家族，是细胞外基质的组成部分，是一种Matrikine(与细胞外基质成分及其能够调节细胞活动的蛋白水解肽有关的术语)。LUM有助于角膜透明，对角膜伤口愈合是必不可少的，但关于这一点是如何实现的知之甚少。我们最近的研究结果表明，转化生长因子受体I型(TGFBR1/ALK5)是一种新的Lum受体。我们旨在研究Lum/Alk5相互作用在调节胚胎发育和发病过程中多种细胞反应中的生物学意义，包括Lum和转化生长因子�信号的多效性。Lumcan结合Alk5并通过减轻对细胞增殖的抑制和上调EGFR配体以维持ERK的激活来促进HTCE(人端粒酶永生化角膜上皮细胞)的伤口愈合。具体目标1将研究Lum/Alk5复合体促进体外伤口愈合的机制。这将通过研究Lum与Alk5结合后TGFBR聚合物的命运，通过评估外调节蛋白上调的作用以及通过鉴定与Lum和/或Src相互作用所需的Alk5结构域(S)来实现。《特殊目的2》将研究Lum/Alk5促进伤口愈合的体内机制。这将通过使用各种转基因小鼠模型来检验Alk5/TGFBR2聚合物是Lum结合和随后促进伤口愈合所必需的假设来实现的。此外，这一目标将进一步研究可能介导伤口愈合的Alk5细胞内结构域。最后，具体目标3将确定和表征用于伤口愈合的治疗性LUMC多肽，特别是在糖尿病患者中看到的受损伤口愈合。这些拟议研究的完成不仅将使我们的理解超越目前由转化生长因子引起的信号级联的中心教条，而且还将识别和表征用于治疗持续性上皮缺陷的治疗性多肽。

DESCRIPTION (provided by applicant): 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 TGFß 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 TGFß, but will also identify and characterize therapeutic peptides for treating persistent epithelium defects.