Development of small-molecule Wnt mimetics for corneal epithelial cell regeneration

项目摘要/摘要以供补充 母体基金的目标是开发小分子Wnt模拟物，以提高扩增效率 功能性人角膜缘干细胞(LSCs)或角膜上皮干/祖细胞(CESCs)用于 移植到人类身上。创建Wnt模拟物的方法是将两个结合在一起的小分子连接起来 两个Wnt共受体，分别为Frizzled型和LRP5/6型。在研究中，我们发现没食子酸和 二倍半没食子酸与Wnt共同受体LRP5/6结合。胞外区有四个b-螺旋桨结构域 WNT分子结合到第二个b-螺旋桨结构域，而DKK蛋白，一组良好的- 建立了WNT拮抗剂，目标是第三个b-螺旋桨区域。所有四个b-螺旋桨区域在结构上都是 相似，但它们是不同的。因此，与第二个b-螺旋桨结构域结合的小分子 亲和力最高的是Wnt抑制剂，而与第三个b-螺旋桨结构域结合的小分子 亲和力最高的是DKK的抑制剂。作为抑制剂的抑制剂，该分子是Wnt的激活剂。vbl.使用 计算和细胞生物学方法，我们建议分析与没食子酸相关的天然产物 它们具有抑制和激活Wnt的活性。因为WNT信号的不适当激活已被牵连 在癌症和许多其他人类疾病中，这项研究可能有助于探索广泛的治疗方法 没食子酸及其相关化合物的应用。

Project Summary/Abstract for supplement The goal of the parent funding is to develop small-molecule Wnt mimics to increase the efficiency of expansion of functional human limbal stem cells (LSCs) or corneal epithelial stem/progenitor cells (CESCs) for transplantation into humans. The approach of creating Wnt mimics is to link two small molecules that bind to two Wnt co-receptors, Frizzled and LRP5/6, respectively. During the study, we found that gallic acid and digallic acid bind to Wnt co-receptor LRP5/6. There are four b-propeller domains in the extracellular domain of LRP5/6. Wnt molecules bind to the second b-propeller domain, whereas DKK proteins, one group of well- established Wnt antagonists, target the third b-propeller domain. All four b-propeller domains are structurally similar, but they are different. Therefore, a small-molecule that binds to the second b-propeller domain with the highest affinity is a Wnt inhibitor, whereas a small-molecule that binds to the third b-propeller domain with the highest affinity is an inhibitor of DKK. An inhibitor of inhibitor, the molecule is a Wnt activator. Using computational and cell biology approaches, we propose to analyze gallic acid-related natural products for their Wnt inhibition and activation activity. As inappropriate activation of Wnt signaling has been implicated in cancers and many other human diseases, the study may be helpful in exploring a broad therapeutic application for gallic acid and related compounds.