Introduction
Chemical genomics uses small molecules to affect the binding of proteins in cells to study gene and translated protein function [3]. Often these studies take the form of a small molecule screen where a large number of small molecules are used in an attempt to alter gene/protein function and the results are assayed for hits in which the gene/protein was successfully affected [1]. These small molecule screens can in some applications be used for the development of new drugs to treat conditions.
Results
A large challenge in using chemical genomics to study Griscelli Syndrome is that the chemical target is not well defined and so a large number and range of small molecules must be used with a high rate of failure [1]. Given the high expected number of failures it doesn't make much sense to invest the time and resources in raising mice to adulthood to test potential molecules on them or their embryos. What I propose instead is a chemical genomic screen using isolated cultured melanocytes. In this screen I propose that each well in the grid contain a GS mutant melanocyte, where the pigment gets trapped in the cell, and growth media. Different small molecules would be tested in different wells. A positive hit would be registered by visually assaying melanocytes and looking for cells that no longer have clumps of melanin trapped on the inside, as in the case of GS, but upon being treated with the small molecule have recovered the ability to transport the pigment outside of the cell.
Discussion
Identification of small molecules that could help recover exocytosis ability of cells even in cultured conditions only would be a huge advancement for GS research. Currently treatment for the disease relies on a bone marrow transplant very early in life. By finding drug targets to explore for treatment the risks of transplant incompatibility and rejection could be mitigated and give patients new options.
References
[1]Eggert, Ulrike S. “The Why and How of Phenotypic Small-Molecule Screens.” Nature Chemical Biology, vol. 9, no. 4, 2013, pp. 206–209., doi:10.1038/nchembio.1206.
[2]“Griscelli Syndrome Type 2.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/4483/griscelli-syndrome-type-2.
[3]XF, Zheng, and Chan TF. “Chemical Genomics: A Systematic Approach in Biological Research and Drug Discovery.” Current Issues in Molecular Biology, 2002, doi:10.21775/cimb.004.033.
[1]Eggert, Ulrike S. “The Why and How of Phenotypic Small-Molecule Screens.” Nature Chemical Biology, vol. 9, no. 4, 2013, pp. 206–209., doi:10.1038/nchembio.1206.
[2]“Griscelli Syndrome Type 2.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/4483/griscelli-syndrome-type-2.
[3]XF, Zheng, and Chan TF. “Chemical Genomics: A Systematic Approach in Biological Research and Drug Discovery.” Current Issues in Molecular Biology, 2002, doi:10.21775/cimb.004.033.
The web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison