Regulatory mechanisms of miR-19b, a novel mediator of T cell autoimmunity: The inappropriate activation and differentiation of CD4 T cells elicits and orchestrates the onset and progression of a wide range of autoimmune diseases. Understanding CD4 T cells'intrinsic regulatory mechanisms has direct implications for the development of novel therapeutics to treat these diseases. While the protein-based signal transduction machinery downstream of T cell antigen recognition has been thoroughly studied, we have recently become aware of a novel and crucial element dictating T cell fate-microRNA (miRNA). mir-17-92 is a gene cluster encoding six different miRNAs, whose important tumor-cell-intrinsic roles in cancer have been well established. However, we have recently discovered that the mir-17-92 cluster also potentiates anti-tumor immunity in a T-cell-intrinsic manner. Furthermore, our preliminary studies indicate that mir-17-92 dictates the progression of CD4 T cell-mediated autoimmunity, principally through the activity of the cluster's mir-19b component.
We aim to discover the molecular mechanism underpinning miR-19b's pro- autoimmune regulatory function, and thereby to establish miR-19b as a potential target for therapy of autoimmune diseases.

Public Health Relevance

In this project, we are focusing on the previously unknown role of microRNA miR-19b in immunoregulation. miR-19b controls CD4 T cells'antigen response by modulating multiple signaling pathways, indicating that it may be a promising target for restoring tolerance under autoimmune conditions. One of the primary targets of this microRNA is MeCP2, the causal factor of the devastating Rett Syndrome, which provides a new angle to understand the etiology of this neuronal development disease. In addition to fundamentally advancing the fields of miRNA biology and T cell biology, this study is very likely to provide new candidate targets for oligonucleotide-based immunotherapy to combat autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI091878-01A1
Application #
8234916
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Rothermel, Annette L
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$252,409
Indirect Cost
$85,742
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Zhang, Baojun; Liu, Si-Qi; Li, Chaoran et al. (2016) MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium. Immunity 44:568-81
Hu, Jing; Sun, Tao; Wang, Hui et al. (2016) MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B. Cancer Cell 29:49-60
Lykken, Erik Allen; Li, Qi-Jing (2016) The MicroRNA miR-191 Supports T Cell Survival Following Common γ Chain Signaling. J Biol Chem 291:23532-23544
Li, Chaoran; Jiang, Shan; Liu, Si-Qi et al. (2014) MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation. Proc Natl Acad Sci U S A 111:E2807-16
Jiang, Shan; Li, Chaoran; McRae, Gabrielle et al. (2014) MeCP2 reinforces STAT3 signaling and the generation of effector CD4+ T cells by promoting miR-124-mediated suppression of SOCS5. Sci Signal 7:ra25
Wang, Hui; Sun, Tao; Hu, Jing et al. (2014) miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways. J Clin Invest 124:4489-502
Lin, Regina; Chen, Ling; Chen, Gang et al. (2014) Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Invest 124:5352-67
Lin, Regina; Kim, Hyoungsu; Hong, Jiyong et al. (2014) Biological evaluation of subglutinol a as a novel immunosuppressive agent for inflammation intervention. ACS Med Chem Lett 5:485-90
Liu, Si-Qi; Jiang, Shan; Li, Chaoran et al. (2014) miR-17-92 cluster targets phosphatase and tensin homology and Ikaros Family Zinc Finger 4 to promote TH17-mediated inflammation. J Biol Chem 289:12446-56
Zhang, Yun; Yang, Pengyuan; Sun, Tao et al. (2013) miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 15:284-94

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