Defining the functional role of a novel MS susceptibility gene, IL7R alpha chain. Multiple sclerosis (MS) is a debilitating neurodegenerative disorder of the central nervous system (CNS) that is thought to be mediated by T-cell autoimmunity and causes neurological inflammation and progressive neurological dysfunction. The `complex disease'nature of MS has made it difficult to identify genes implicated in, and understand the underlying molecular mechanisms of the disease. We have recently generated exciting new data which has identified significant association with MS of a SNP within the interleukin 7 alpha chain receptor gene (IL7R1). Further, we have proven that the associated SNP leads to increased skipping of the transmembrane domain of the protein, resulting in increased production of the soluble form of IL7R1. The objective of this grant is to build upon this ground breaking discovery. We propose to identify the cis- and trans- factors involved in exon 6 IL-7R1 splicing, determine the effect that exon skipping has upon interleukin 7 (IL-7) and thymic stromal lymphopoietin (TSLP) pathways, and the influences that this has upon naove T- cell differentiation and memory T-cell homeostasis. By elucidating these mechanisms we hope to gain a better understand IL7R1 is functionally implicated in the etiology of MS.
Multiple sclerosis (MS) is a debilitating neurodegenerative disorder of the central nervous system that affects more than 400,000 individuals in the United States. We have recently generated exciting new data in which have identified a gene (IL-7R) implicated in MS. This grant builds upon our discovery by investigating of the functional that the candidate gene plays in immune response and how this may contribute to MS. We propose to compare the function of IL-7R in specific immune cells in MS patients and control individuals to identify how IL-7R influences immune cell maintenance.
| Galarza-Muñoz, Gaddiel; Briggs, Farren B S; Evsyukova, Irina et al. (2017) Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk. Cell 169:72-84.e13 |
| Inoue, Makoto; Chen, Po-Han; Siecinski, Stephen et al. (2016) An interferon-?-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage. Nat Neurosci 19:1599-1609 |
| Evsyukova, Irina; Bradrick, Shelton S; Gregory, Simon G et al. (2013) Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA 19:103-15 |
| Evsyukova, Irina; Somarelli, Jason A; Gregory, Simon G et al. (2010) Alternative splicing in multiple sclerosis and other autoimmune diseases. RNA Biol 7:462-73 |
