Inflammation js the body's natural protective response to infection or injury, but abnormal or uncontrolled inflammatory responses can do more harm than good. A breakdown in the appropriate regulation of inflammation underlies a wide range of common diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and septic shock. The expression of pro-inflammatory genes by cells in the immune system is the most crucial step in the development of inflammation. Although significant progress has been made, the mechanism of pro-inflammatory gene expression is still not fully understood. The long- term objective of this proposal is to gain an understanding of the regulation and function of microRNA (miRNA), a newly identified group of short non-coding single-stranded RNA, in the expression of pro- inflammatory genes. It is knownthat pro-inflammatory genes such as tumor necrosis factor, interleukin-1, arid cyclooxygenase 2 are controlled at multiple levels of gene expression, one of the most important of which is at the regulation of then- mRNAstability. Quick mRNAdegradation of these pro-inflammatorygenes serves as a mechanism to control the level of pro-inflammatory molecules. AU-rich elements (AREs) located in the 3'untranslated region of these short-lived mRNAs dictate their degradation. Ourrecent study revealed that Dicer and Argonaute (Ago/eif2C) family members, components involved in microRNA(miRNA) processing and function, are required for the rapid decay of mRNA that contain AREs (ARE-mRNA). Furthermore, we found miR16, a human miRNAwith a sequence that is partially complementaryto the ARE sequence, to be required for ARE-mRNAturnover. The requirement of miR16 in ARE-mRNA decay in resting cells suggests a physiological 'housekeeping'function of miR16 in which it prevents high basal levels of pro-inflammatory gene expression. This proposal outlines a study into the mechanism of miRNA-regulated cytokine gene expression, with an emphasis on how inflammatory stimuli induce stabilization of ARE-mRNA by blocking miRNA-mediated mRNA degradation. In this research plan, we will also evaluate the overall function of miR16 by genome-wide identifying and classifying of miR16-targeted genes. To achieve our aims, we will utilize a combination of genetic, biochemical, and molecular biological approaches. The work proposed in this application will contribute to a better understanding of pro-inflammatory gene expression. Understanding the function of miRNA in mRNA stability of pro-inflammatory genes should provide new avenues for developing novel anti-inflammatoryagents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068896-05
Application #
8008824
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$455,501
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Lu, Jiawei; Wu, Xiurong; Hong, Mao et al. (2013) A potential suppressive effect of natural antisense IL-1β RNA on lipopolysaccharide-induced IL-1β expression. J Immunol 190:6570-8
Seit-Nebi, Alim; Cheng, Wei; Xu, Hong et al. (2012) MLK4 has negative effect on TLR4 signaling. Cell Mol Immunol 9:27-33
Zheng, Min; Wang, Yan-Hai; Wu, Xiao-Nan et al. (2011) Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat Cell Biol 13:263-72
Lee, Sangun; Wang, Yanhai; Kim, Sung Ouk et al. (2011) AMPD3 is involved in anthrax LeTx-induced macrophage cell death. Protein Cell 2:564-72
Ono, Koh; Kuwabara, Yasuhide; Han, Jiahuai (2011) MicroRNAs and cardiovascular diseases. FEBS J 278:1619-33
Wu, Xiao-Nan; Wang, Xue-Kun; Wu, Su-Qin et al. (2011) Phosphorylation of Raptor by p38beta participates in arsenite-induced mammalian target of rapamycin complex 1 (mTORC1) activation. J Biol Chem 286:31501-11
Otsuka, Motoyuki; Kang, Young Jun; Ren, Jianlin et al. (2010) Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease. Gastroenterology 138:1255-65, 1265.e1-9
Hong, Lixin; Lai, Maoyi; Chen, Michelle et al. (2010) The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene-induced senescence. Cancer Res 70:8547-57
Wu, Chia-Cheng; Wu, Xiaohua; Han, Jiahuai et al. (2010) p38γ regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage. Protein Cell 1:573-83
Martins, Andrew; Han, Jiahuai; Kim, Sung O (2010) The multifaceted effects of granulocyte colony-stimulating factor in immunomodulation and potential roles in intestinal immune homeostasis. IUBMB Life 62:611-7

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