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.

Public Health Relevance

The goal of this proposed research is to develop potent Wnt mimics small-molecule to increase the efficiency of the self-renewal of functional human limbal epithelial stem/progenitor cells for transplantation into humans. Thus, the proposed research will enable the initiation of a more effective patient-specific stem cell-based therapy for treating limbal stem cell deficiency?related disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY028557-01A1
Application #
9597186
Study Section
Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section (BNVT)
Program Officer
Mckie, George Ann
Project Start
2018-09-30
Project End
2022-08-31
Budget Start
2018-09-30
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095