Atherosclerosis is a pathogenic consequence of uncontrolled inflammation of the resident cells of vessel wall. Using cell-based model we showed that ribosomal protein L13a-dependent translational silencing pathway could terminate the expression of a group of inflammatory genes. In this proposal we will test whether this mechanism can resolve inflammation. We have demonstrated that IFN-3 induced synthesis of Ceruloplasmin (Cp) and a group of other inflammatory proteins in monocytic cells is under translational control. Further, we discovered a crucial role of ribosomal protein L13a and its release from 60S ribosome in the formation of IFN- Gamma-Activated Inhibitor of Translation (GAIT) complex. The translational silencing mechanism relies on the recognition of L13a-dependent GAIT complex by the GAIT element present in the 3

Public Health Relevance

Uncontrolled inflammation is the cause of many diseases such as atherosclerosis or cardiovascular disease. This research will uncover the insight about the endogenous cellular mechanisms to control the expression of inflammatory molecules and help to generate novel therapeutic agents against inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079164-07
Application #
8132457
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
2005-03-01
Project End
2015-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
7
Fiscal Year
2011
Total Cost
$354,910
Indirect Cost
Name
Cleveland State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
010841617
City
Cleveland
State
OH
Country
United States
Zip Code
44115
Basu, Abhijit; Jain, Niyati; Tolbert, Blanton S et al. (2017) Conserved structures formed by heterogeneous RNA sequences drive silencing of an inflammation responsive post-transcriptional operon. Nucleic Acids Res 45:12987-13003
Poddar, Darshana; Kaur, Ravinder; Baldwin 3rd, William M et al. (2016) L13a-dependent translational control in macrophages limits the pathogenesis of colitis. Cell Mol Immunol 13:816-827
Golovko, Andrei; Kojukhov, Artyom; Guan, Bo-Jhih et al. (2016) The eIF2A knockout mouse. Cell Cycle 15:3115-3120
Mazumder, Barsanjit; Poddar, Darshana; Basu, Abhijit et al. (2014) Extraribosomal l13a is a specific innate immune factor for antiviral defense. J Virol 88:9100-10
Basu, Abhijit; Poddar, Darshana; Robinet, Peggy et al. (2014) Ribosomal protein L13a deficiency in macrophages promotes atherosclerosis by limiting translation control-dependent retardation of inflammation. Arterioscler Thromb Vasc Biol 34:533-42
Poddar, Darshana; Basu, Abhijit; Baldwin 3rd, William M et al. (2013) An extraribosomal function of ribosomal protein L13a in macrophages resolves inflammation. J Immunol 190:3600-12
Das, Priyanka; Basu, Abhijit; Biswas, Aditi et al. (2013) Insights into the mechanism of ribosomal incorporation of mammalian L13a protein during ribosome biogenesis. Mol Cell Biol 33:2829-42
Komar, Anton A; Mazumder, Barsanjit; Merrick, William C (2012) A new framework for understanding IRES-mediated translation. Gene 502:75-86
Basu, Abhijit; Das, Priyanka; Chaudhuri, Sujan et al. (2011) Requirement of rRNA methylation for 80S ribosome assembly on a cohort of cellular internal ribosome entry sites. Mol Cell Biol 31:4482-99
Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen (2010) Translation control: a multifaceted regulator of inflammatory response. J Immunol 184:3311-9

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