Structure/Function Relationship of the Lumican Gene

描述（由申请人提供）：Lumican （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，并作为基质因子（一个与ECM成分及其能够调节细胞活性的蛋白水解肽有关的术语）。Lum有助于角膜透明，对角膜伤口愈合至关重要，但很少有人知道这是如何实现的。我们最近的研究结果表明TGFß I型受体（TGFBR1/ALK5）是一种新的Lum受体。我们的目的是研究Lum/ALK5相互作用在胚胎发育和发病过程中调控各种细胞反应的生物学意义，说明Lum和TGF信号通路的多效性。Lumican结合ALK5，通过减轻对细胞增殖的抑制和上调egfr配体来维持ERK的激活，促进HTCE（人类端粒酶永活角膜上皮）细胞的伤口愈合。特异性目的1将研究由Lum/ALK5复合物引发的体外伤口愈合增强的机制。这将通过检查TGFBR聚合物在Lum与ALK5结合后的命运，通过评估表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结构域来实现。特异性目的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。除此之外，我们还将进一步研究可能介导伤口愈合的ALK5细胞内结构域。最后，Specific Aim 3将着手确定和表征用于伤口愈合的治疗性LumC肽，特别是糖尿病患者伤口愈合受损的LumC肽。这些研究的完成不仅将扩大我们对TGFß引发的信号级联反应的理解，而且还将确定和表征治疗持续性上皮缺陷的治疗肽。

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.