There is rapidly accumulating evidence for a pivotal role of microRNAs (miRs) in regulating immune cell development/function. Recently we made an important observation that miR223 was increased not only in the diseased central nerve system (CNS) but also in the peripheral immune compartments of EAE mice, an animal model of multiple sclerosis (MS). Notably, increased miR223 expression in EAE spinal cord was blocked by an anti-immune agent 1,25(OH)2D3. Moreover, miR223 in the MS patient's blood cells was elevated. These findings point to a pathogenic role of miR223 in CNS autoimmune inflammation. Now we have obtained compelling evidence to support this premise;namely, abrogation of miR223 either globally or conditionally in hematopoietic stem cell-derived immune cells resulted in a remarkable resistance to EAE. These breakthroughs establish miR223 as a novel miR in regulating CNS autoimmune inflammation. Our goal is to further evaluate miR223's function in pathogenesis of EAE and identify the mechanisms of the miR223's action. We will first verify that autoantigen-elicited miR223 expression is the cause rather than the result of EAE. We will address this issue by studying the temporal sequence in onset of miR223 induction and demyelination, followed by investigating if miR223 functional blockade will reduce demyelination. We will then identify the cellular mechanism by which miR223 promotes EAE. Specifically we will test the hypothesis that miR223 promotes axonal demyelination by enhancing pathogenic Th17 and M1 macrophage polarization using conditional knockout and cell-specific rescue. Finally, we will identify and functionally characterize the downstream mediators of miR223, namely the miR223 target genes, in EAE. We have identified a list of potential miR223 targets using carefully designed screening strategies. We will focus on two potentially neuroprotective genes, monocyte enhancer factor (Mef2c), a known miR223 target, and the lipopolysaccharide responsive beige-like anchor gene (Lrba), a potentially novel target. Our work will likely uncover new mechanisms by which autoimmunity develop in CNS. In terms of the clinical relevance of this work, identification of the role and mechanism of the action of miR223 in EAE could potentially lead to development of miR223-based therapy for treatment of MS, which occurs in both civilian and military-veteran populations.

Public Health Relevance

Multiple sclerosis (MS) is a very common brain disease for which there is no cure thus far. The importance of MS to military-veteran population is addressed elegantly in a very recent comprehensive study conducted by the VA researchers. According to this study, the annual incident rate per 100,000 military-veteran population during the Gulf War era (1990-2007) is 7.31 for man and 24.69 for women. The age of MS onset in military-veteran population rages from 17 to 50 with an average of 30. There is a clear trend of increase in MS incidence among military-veteran population. Considering the prevalence of MS in military-veteran population, our proposed work on MS is highly relevant to the VA mission. If we find that miRNA223 contributes to development of EAE, an mouse model of MS, it could potentially lead to development of new therapy for MS.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (NURB)
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VA Loma Linda Healthcare System
Loma Linda
United States
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