Multiple Sclerosis (MS) is an autoimmune disorder of the central nervous system typified by axonaldemyelination and neuronal death. To date, there is no effective treatment to cure the disease, and theavailable therapies do not alter the outcome of the disease. The development of better therapeutic optionsrequires in-depth understanding of the molecular mechanisms leading to disease development andprogression. Our group previously discovered a single nucleotide polymorphism (SNP, rs6897932) within exon6 of the IL-7 receptor alpha chain (IL7R) that is strongly associated with the risk of developing MS. Our groupfurther showed that the MS-associated allele of the SNP increases skipping of exon 6 both in vitro and in vivo,leading to increased production of a secreted receptor (sIL7R) that is unable to activate the IL-7 signalingpathway. Importantly, sIL7R has been linked to the disease in both human patients and animal models. Theseresults directly implicate splicing of IL7R to the pathogenesis of MS, and posit the trans-acting factorscontrolling its splicing as candidate MS susceptibility genes. I have uncovered two of the trans-factorscontrolling IL7R exon 6 splicing: the RNA helicase DDX39B, which activates exon inclusion, and thepolypyrimidine tract binding protein (PTBP1), which represses it. Furthermore, we uncovered several SNPs inthe DDX39B gene region that are associated with MS, thereby establishing DDX39B is itself a risk factor forMS. None of the associated SNPs are located within the coding sequence of the gene, suggesting that one ormore of these SNPs may contribute to the disease association by modifying DDX39B expression. Throughbioinformatics and gene expression analyses, I have uncovered mRNA isoforms encoding either the full-lengthprotein or a novel short protein, and several mRNA isoforms that are candidate targets for nonsense-mediateddecay. Importantly, I have established two of the SNPs could alter expression levels of these isoforms. The goal of this proposal is to provide functional links connecting DDX39B to the pathogenesis of MS.Specifically, I aim to: 1) elucidate its role in the regulation of IL7R exon 6 splicing; 2) understand the functionalroles of the different protein isoforms; and 3) uncover the SNPs responsible for its association with MS. I willcombine biochemical and genetic approaches to elucidate the mechanism by which DDX39B activates exon 6splicing, and to characterize the functional roles of the protein isoforms. I will test the impact of selected SNPson DDX39B expression by combining in vivo gene expression analysis and functional studies using reporterminigenes. Successful completion of this research will advance our current understanding of the molecularunderpinnings of MS, in particular by functionally linking DDX39B to the pathogenesis of MS, and providing afunctional characterization of the DDX39B gene. Given that DDX39B has been associated with numerousautoimmune disorders, our results could be relevant to the mechanistic etiology of other autoimmune diseases.

Public Health Relevance

Our group has previously implicated alternative splicing of the interleukin 7 receptor (IL7R) in thepathogenesis of Multiple Sclerosis (MS). We uncovered the RNA helicase DDX39B as an activator of IL7Rsplicing; and further established it is itself a risk factor for MS. This proposal focuses on elucidating thefunctional links of DDX39B with the pathogenesis of MS; and perhaps; of many autoimmune disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32NS087899-02
Application #
9073091
Study Section
Special Emphasis Panel (ZRG1-F07-K (20))
Program Officer
Utz, Ursula
Project Start
2015-06-01
Project End
2017-11-30
Budget Start
2015-06-01
Budget End
2015-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$25,765
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Barrows, Nicholas J; Campos, Rafael K; Powell, Steven T et al. (2016) A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. Cell Host Microbe 20:259-70