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Darshana Poddar_Dissertation.pdf (3.28 MB)

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Study of Role of Ribosomal Protein L13a in Resolving Inflammation

Poddar, Darshana, Ph.D.
http://rave.ohiolink.edu/etdc/view?acc_num=csu1400587453

Abstract Details

2014, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
Inflammation is an obligatory attempt of the host immune system to protect the body against infection. However, unregulated synthesis of pro-inflammatory products can have detrimental effects. Though mechanisms which contribute to inflammation are well appreciated, those that resolve inflammation are poorly understood. Therefore, understanding the molecular basis of such pathways will provide an entirely novel approach to treat and prevent inflammatory diseases. Transcript-selective translational control can regulate the expression of a set of inflammatory genes. We have identified one such mechanism in a novel animal model which relies on the abrogation of ribosomal protein L13a-dependent translational silencing by creating macrophage-specific L13a-knockout mice where resolution of inflammation is severely compromised. We have used these knockout mice to study two different kinds of inflammation: LPS induced systemic inflammation and dextran sodium sulphate (DSS) induced experimental colitis. Upon LPS induced endotoxemia, these mice displayed high mortality rates and severe symptoms of inflammation such as infiltration of immune cells in the peritoneum and major organs leading to tissue destruction. These animals also exhibited high serum levels of TNF-a, blood urea nitrogen (BUN), aspartate aminotransferase (AST) and several other markers of inflammation. Macrophages from these knockouts showed unregulated synthesis of several chemokines (e.g., CXCL13, CCL22, CCL8 and CCR3) and increased polysomal abundance of these mRNAs due to the abrogation of their translational silencing. Upon DSS induced colitis, these knockout mice demonstrated higher susceptibility to colitis displaying reduced survival, significant weight loss, enhanced rectal bleeding and diarrhea. Histopathology analysis of tissue sections from the knockouts showed disruption of epithelial crypts in the colon with infiltration of macrophages in colon and spleen sections. Additionally, elevated levels of several chemokines and cytokines were found to be associated with the serum and colons of the DSS administered knockout animals. Therefore, based on these observations, we hypothesize that L13a-dependent translational silencing has evolved as an endogenous defense mechanism in monocytes and macrophages against uncontrolled inflammatory response and disruption of this pathway can severely impair the resolution phase of inflammation.
Barsanjit Mazumder, Ph.D. (Advisor)
Crystal Weyman, Ph.D. (Committee Member)
Anton Komar, Ph.D. (Committee Member)
William Baldwin, M.D., Ph.D. (Committee Member)
Roman Kondratov, Ph.D. (Committee Member)
Aimin Zhou, Ph.D. (Committee Member)
Animals; Biology; Immunology; Molecular Biology
L13a; inflammation; GAIT; resolution of inflammation; DSS; endotoxemia; LPS

Recommended Citations

Citations

  • Poddar, D. (2014). Study of Role of Ribosomal Protein L13a in Resolving Inflammation [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1400587453

    APA Style (7th edition)

  • Poddar, Darshana. Study of Role of Ribosomal Protein L13a in Resolving Inflammation . 2014. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1400587453.

    MLA Style (8th edition)

  • Poddar, Darshana. "Study of Role of Ribosomal Protein L13a in Resolving Inflammation ." Doctoral dissertation, Cleveland State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1400587453

    Chicago Manual of Style (17th edition)

csu1400587453
539
© 2014, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.