Identifying new therapies and understanding the pathogenesis of FSHD

Barbara Page
Barbara Page

An update by Barbara D Page on the work done for the first of a 2-year project titled Using model organisms to identify new therapies and understand the pathogenesis of FSHD, funded by Friends of FSH Research (see Grants for 2010).

During my past year as an FSH Research Scholar in Dr. Stephen Tapscott’s laboratory at the Fred Hutchinson Cancer Research Center, I have focused on using two different model organisms to better understand facioscapulohumeral muscular dystrophy (FSHD). The goals of my research are:

  1. to develop new therapies to treat patients with this disease by performing high throughput small molecule screens and
  2. to provide greater understanding as to how DUX4, a gene that is inappropriately expressed in patients with FSHD, functions by studying its role in normal development.

Recent experiments suggest that FSHD may be caused in part by the inappropriate expression of DUX4 due to a loss of gene silencing. Therefore, a possible line of therapy for patients with FSHD would be the use of drugs that could reestablish silencing of the DUX4 gene. As a first step to identify such drugs, I am using the yeast S. pombe to screen for small molecules that can increase gene silencing. During this last year, I have designed and successfully optimized this screen to work in a high throughput format. During the next year, working in collaboration with researchers at the National Institutes of Health’s Chemical Genomics Center, we will initiate a pilot screen for small molecules that can enhance gene silencing. These studies will lay the foundation for testing a much larger library of thousands of compounds to identify potential therapeutics for patients with FSHD.

My second project involving the model organism C. elegans takes advantage of the numerous genetic tools available in this organism to investigate how genes like DUX4 function in normal development. We have discovered a DUX4-like gene in C. elegans, which we have named dux-1. My studies have shown that the C. elegans dux-1 gene is critical for male fertility. In the male germ line, the dux-1 gene and genes that regulated cell death work together to remove parts of the spermatocyte in order to form compact, functional sperm. Additionally, I have observed that inappropriate expression of dux-1 during development of the embryo causes muscle paralysis. Taken together, these results suggest that dux-1 could lead a program of organized cellular destruction, and that muscle is particularly sensitive to the activation of this pathway. Our above observations of dux-1 function in C. elegans suggest that DUX4 in human cells might orchestrate a “demolition squad” to remove and recycle cellular components. Greater detail about dux-1’s targets and collaborators as well as understanding the sensitivity of muscle to its expression will hopefully lead to new lines of promising experimental research for patients affected with FSHD.