NFATc-Down's Syndrome

This semester long process has provided a great opportunity to delve into the world of genomics, proteomics, and bioinformatics.  It provided an opportunity to look at many the facets and aspects of NFATc not only in terms of its role in Down's Syndrome but also its general properties and functions. 
       Using programs such as NCBI to find the sequence of the gene and protein was just a start.  By gaining access to the nucleotide and amino acid sequences many other algorithmic programs could be utilized to further study NFATc.  Plugging the sequence into Homologene provided examples of the NFATc protein in other organisms.  This is of great use because by knowing how conserved a gene is in other organisms a proper model can be developed for future experiments on this gene of interest.  For example, in the case of NFATc the mouse would provide an excellent system for which to study NFATc and its role in the body.  This was already shown in the case of Arron et al. where they utilized mice to discover NFATc's role in Down's Syndrome.
     In the case of the protein specifically, if not much is known about its function there is a ton of information that can be gained using these online algorithms.  Gene Ontology databases can provide functional characteristics as well as localization information about a specific protein.  In the case of NFATc it also established a connection to small molecule binding (FK506) which lead to the discovery of NFATc's direct impact on the immune system (a common deficiency found in Down's Syndrome individuals).
    Programs such as SMART and PFAM allow for a better understanding of the function of the protein.  With NFATc it uncovered characteristic domains of transcription factors revealing a common DNA binding site and the site of phosphorylation of the protein (the area that regulates the function of the protein).  The location of these domains is very important when considering the function of this protein and searching for ways to regulate NFATc in the presence of an overdosage of the 21 chromosome.  Knowing where these domains are located could lead to a better understanding of how NFATc is controlled and regulated.
     Probably the most useful aspect of this project was the protein interaction networks that were discovered using STRING. Not only did they reveal and confirm interactions that were already hypothesized (DSCR1 and CALN) but they also provided examples of other proteins that play a role in pathways involving NFATc.  For example, all of the interleukin proteins that are shown to interact with NFATc provide further evidence into its importance in immune response.  STRING also gives an opportunity for establishing new interaction profiles, as was the case with FOXP2 and GSK3B, to begin to discern pathways for future areas of research and discovery.

This project has provided a lot of insight into Down's Syndrome and the role that NFATc plays in the development of the disease.  There is still plenty of work and discovery left for this disease/gene pair, however, and listed below are some examples of future directions for research.
       There is still much research to be done on the interactions of proteins on the 21st chromosome.  Perhaps some experimental Y2H screens or affinity purification assays could be utilized to get a better idea of which proteins are interacting with proteins on the 21st chromosome, so that more studies like that of Arron et al. could be preformed.  If more proteins that interact could be identified, then knock out screens and overexpression profiles could be completed to see what effects overdosage is having.
        It would also be interesting to test the effects of overexpressing genes in combination with chromosome 21 overexpression to search for some therapeutic relief for Down's Syndrome individuals.  Either overexpressing calcineurin or NFATc in trisomy 21 mice to determine if there could be any alleviation of the symptoms associated with Down's Syndrome. It may be most useful here to overexpress calcineurin as it directly interacts with DSCR1, while overexpressing NFATc may cause other residual side effects as it is a very important transcription factor to many functions.
        Finally, there is a potential for drug therapies as well.  Searching for small molecules that interact with DSCR1, or other proteins from the 21st chromosome, to cut back on inhibitory effects on the NFATc pathway could go a long way in helping reduce the many symptoms of Down's Syndrome. 
        It will be interesting to see what the future holds for research on Down's Syndrome and NFATc specifically.  It is clear that there is already a ton of information available about this topic, however, there is still a long way to go and many possibilities for further developments.