MicroRNA (miRNA), have been demonstrated recently to be pivotal in regulating immune responses. Among them, miR-155 is one of the most prominent miRNAs in the immune system. Genetic loss-of-function studies have demonstrated that miR-155 controls multiple aspects of the immune responses through silencing a wide range of targets in various immune cell populations. Our previous work suggested that Foxp3 drives high expression of miR-155 and, thereby promotes the competitive fitness of Treg cells by inducing SOCS1 down-regulation. Subsequent studies conducted by other groups have implied a role for the miR-155/SOCS1 axis in tuning macrophage responsiveness to LPS-induced endotoxin tolerance as well as cytokine production by dendritic cells. However, since miRNAs mediate their effects through targeting a broad range of mRNA species, diverse immune response related phenotypes in miR-155 deficient mice can be attributed to changes in miR-155 target genes other than SOCS1. Here, we propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to comprehensively examine the role for miR-155-mediated SOCS1 regulation. First, we will examine the combined effects of SOCS1 deficiency/haploinsufficiency and miR-155 deficiency to see if aspects of the observed miR-155 phenotype are reversed by loss of SOCS1 function. Next, by generating a new mouse model with mutations specifically disrupting the interaction between miR-155 and SOCS1 gene (SOCS1KI/KI mice) and by comparing these mice to miR-155-deficient mice, we will be able to isolate the effects of miR-155 on a single target and to explore the biological significance of SOCS1 repression in miR-155-mediated immune regulation. Moreover, as miR-155 has been strongly implicated in promoting inflammatory responses required for the development of autoimmunity, in the second specific aim, we will elucidate the role of SOCS1 repression by miR-155 in EAE, a well-established animal model of multiple sclerosis. The availability of SOCS1KI/KI mice affords the opportunity to examine the contribution of miR-155-mediated SOCS1 repression to the control of autoimmune disease. Moreover, using T cell transfer experiments as well as mixed BM chimeras studies, more refined insights into the respective role of miR-155-mediated SOCS1 repression within different hematopoietic lineages will be determined. Finally, we will investigate effector mechanisms underlying miR-155-mediated SOCS1 repression in promoting EAE disease phenotype. The proposed studies will greatly extend our fundamental knowledge of SOCS1 repression in miR-155-mediated immune regulation and provide further insights into this specific miRNA-target partnership in regulating human health and disease.
The proposed studies aim to facilitate basic understanding of the effects of miRNA on a single target and to explore the biological significance of such regulation in the context of autoimmunity. The results obtained from these studies will provide critical insights into manipulating miRNA-dependent post-transcriptional regulation as a novel therapeutic approach for not only autoimmunity but also many other immunological human diseases.
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