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

项目摘要/补充摘要 母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（LSC）或角膜上皮干/祖细胞（CESC）， 移植到人类。创建Wnt模拟物的方法是将两个小分子连接到 两种Wnt共受体，分别为Frizzled和LRP 5/6。在研究过程中，我们发现没食子酸和 二没食子酸与Wnt共受体LRP 5/6结合。在胞外区有四个b-propeller结构域 LRP 5/6 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- 已建立的Wnt拮抗剂靶向第三个b-螺旋桨结构域。所有四个b螺旋桨域在结构上都是 相似，但它们不同。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，而结合到第三个b-螺旋桨结构域的小分子， 最高亲和力是DKK的抑制剂。抑制剂的抑制剂，该分子是Wnt激活剂。使用 计算和细胞生物学方法，我们建议分析没食子酸相关的天然产物， 它们的Wnt抑制和激活活性。由于Wnt信号传导的不适当激活与 在癌症和许多其他人类疾病中，这项研究可能有助于探索一种广泛的治疗方法， 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.