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

用于角膜上皮细胞再生的小分子Wnt模拟物的开发

• 批准号: 9811997
• 负责人: Sophie Deng
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811997
• 关键词: 3T3 Cells; Affinity; Animal Model; Area; Autologous; Autologous Transplantation; Bilateral; Binding; Blindness; Cell Culture Techniques; Cell Nucleus; Cell Therapy; Cells; Cellular Assay; Characteristics; Clinical; Cornea; Corneal Diseases; Cytoplasmic Protein; Development; Dimerization; Disease; Dsh protein; Epithelial; Epithelial Cells; FDA approved; Generations; Genes; Goals; Graft Survival; Growth; Human; Hybrids; Immune; In Vitro; Keratoplasty; LDL-Receptor Related Proteins; Length; Ligands; Link; Lipoproteins; Maintenance; Methods; Modeling; Mus; Natural regeneration; Oryctolagus cuniculus; Outcome; Patients; Pharmacologic Substance; Population; Probability; Procedures; Process; Proteins; Reagent; Reporting; Research; Safety; Serum; Signal Transduction; Stem cell transplant; Stem cells; Structure; System; Testing; Therapeutic; Time; Transplantation; Vision; WNT Signaling Pathway; Wnt proteins; base; beta catenin; blind; conjunctiva; corneal epithelial stem cells; corneal epithelium; cost; crosslink; drug discovery; experimental study; follow-up; improved; inhibitor/antagonist; limbal; mimetics; novel; ocular surface; prevent; receptor; reconstruction; self-renewal; small molecule; stem; stem cell therapy; success; tissue culture

Abstract Limbal stem cell deficiency (LSCD) is a major cause, either primary or secondary, of significant visual loss and blindness in many common corneal disorders. Transplantation of autologous limbal stem cells (LSCs) expanded in tissue culture has successfully restored vision and revolutionized the treatment of LSCD. A higher expansion efficiency of the stem/progenitor cell population in culture corresponds to a greater probability of long-term graft survival. The long-term goal of our study is to develop small molecules that can govern LSC self-renewal and differentiation and be used as therapeutic reagents for stem cell-based treatments of LSCD– related disorders. The most efficient expansion method requires feeder cells that provide a proper microenvironment to support the growth of LSCs. Among the external signaling that the feeder cells provide to the LSCs is the Wnt signaling. The central hypothesis of this project is that small molecules can be developed to mimic the Wnt proteins and activate Wnt signaling in the cells. We further propose that these small molecules will increase the efficiency of ex vivo expansion of functional human LSCs. The goal of this application is to use a structure-based drug discovery approach to develop potent Wnt mimics small molecule and to test their ability to increase the efficiency of ex vivo LSC expansion. Because the maintenance of stem cell characteristics in the process of culture expansion is essential for the success of ocular surface reconstruction, the small molecules generated in this project will serve as a platform for the development of novel pharmaceutical reagents for treating other corneal epithelial disorders.

摘要 角膜缘干细胞缺乏症（LSCD）是导致严重视力丧失的主要原因，无论是原发性还是继发性， 许多常见的角膜疾病导致失明。自体角膜缘干细胞（LSC）移植 在组织培养中扩大的这种方法已经成功地恢复了视力，并彻底改变了LSCD的治疗方法。更高 培养物中干/祖细胞群的扩增效率对应于 移植物的长期存活率。我们研究的长期目标是开发能够控制LSC的小分子 自我更新和分化，并用作LSCD的基于干细胞的治疗的治疗试剂， 相关疾病。最有效的扩增方法需要饲养细胞，其提供适当的扩增能力。 微环境，以支持LSC的生长。在饲养细胞提供的外部信号中 LSC是Wnt信号。这个项目的中心假设是小分子可以被开发出来 来模拟Wnt蛋白并激活细胞中的Wnt信号。我们进一步建议，这些小 这些分子将增加功能性人LSC的离体扩增的效率。这个目标 应用是使用基于结构的药物发现方法来开发有效的Wnt模拟小分子 并测试它们提高离体LSC扩增效率的能力。因为阀杆的维护 培养扩增过程中的细胞特性对于眼表的成功至关重要 重建，在这个项目中产生的小分子将作为一个平台的发展， 用于治疗其它角膜上皮疾病的新的药物试剂。