This is a renewal application aimed at investigating the epigenetic pathways through which botanicals used commonly as CAM, suppress inflammation. During the previous funding cycle, we have made outstanding progress identifying novel cellular and molecular pathways through which botanicals mediate their anti- inflammatory properties. Inflammation can trigger a wide range of diseases including autoimmune, cardiovascular, neurodegenerative, obesity, and certain types of cancer. For this reason, it is not only critical to uncover as-yet-unknown immune mechanisms and mediators of inflammation but also find novel treatment modalities. Because currently there are no medications that can effectively treat chronic inflammation and associated pain without significant side effects, our proposed studies are highly significant. Traditionally, the medicine practiced in India (Ayurveda) and China have used herbal products to treat inflammatory disorders. Also, more than 25% of the pharmaceuticals are derived from plants, which suggests that botanicals offer novel modalities against inflammation. Epigenetic modifications of chromatin and DNA have been shown recently to play a critical role in the regulation in human pathologies, including inflammation. Thus, the concept that botanicals used as CAM may mediate their effects through epigenetic regulation is highly innovative. The primary objective of the Center is to test the overarching hypothesis that botanicals currently used as CAM, regulate the epigenetic signaling pathways through interactions with specific receptors on immune cells to modulate gene expression leading to amelioration of inflammation. This will be tested using four research projects, 1) Identifying epigenetic pathways through which resveratrol (RES) triggers myeloid- derived suppressor cells (MDSCs) in the regulation of neuroinflammation. 2) Epigenetic regulation of Nrf2 signaling pathway in American ginseng (AG)-mediated suppression of inflammation in the colon and colon cancer. 3) Elucidation of the epigenetic mechanisms underlying dietary indole-mediated amelioration of inflammation in the colon specifically addressing how indoles activate AhR to promote Tregs and suppress Th17 cells. 4) Identifying the role of Sparstolonin B (a compound isolated from Sparganium stoloniferum tubers), as a TLR2 and TLR4 antagonist, thereby suppressing inflammation in the liver through epigenetic regulation. The projects are highly integrated and synergistic, all addressing epigenetic pathways so that the data generated from one project will benefit other projects. The projects will use an Administrative Core which will coordinate all activities of the Center and ensure scientific and programmatic progress. All projects will also use an Analytical Core which will perform genome-wide DNA methylation, histone methylation/acetylation, microRNA arrays, immune monitoring, bioinformatics and natural product integrity testing. Together, our CAM Center will identify epigenetic biomarkers and pathways through which botanicals suppress inflammation thereby paving the way for better treatment modality against inflammatory diseases.

Public Health Relevance

Inflammation is considered to be the underlying cause of most clinical disorders for which currently no effective treatment exists. Our goal is to identify the mechanisms through which botanicals suppress inflammation, specifically looking at chemical reactions outside the DNA that can influence the functions of genes and cells.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
2P01AT003961-06A1
Application #
8739821
Study Section
Special Emphasis Panel (ZAT1)
Program Officer
Pontzer, Carol H
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Columbia
State
SC
Country
United States
Zip Code
29208
Zhou, Juhua; Chaudhry, Hina; Zhong, Yin et al. (2015) Dysregulation in microRNA expression in peripheral blood mononuclear cells of sepsis patients is associated with immunopathology. Cytokine 71:89-100
Sido, Jessica Margaret; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2015) Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease. Int Rev Immunol 34:403-14
Jackson, Austin R; Hegde, Venkatesh L; Nagarkatti, Prakash S et al. (2014) Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1. J Leukoc Biol 95:609-19
Jackson, Austin R; Nagarkatti, Prakash; Nagarkatti, Mitzi (2014) Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PLoS One 9:e93954
Zhou, Juhua; Nagarkatti, Prakash; Zhong, Yin et al. (2014) Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS One 9:e94075
Singh, Udai P; Singh, Narendra P; Guan, Hongbing et al. (2014) The emerging role of leptin antagonist as potential therapeutic option for inflammatory bowel disease. Int Rev Immunol 33:23-33
Yang, Xiaoming; Hegde, Venkatesh L; Rao, Roshni et al. (2014) Histone modifications are associated with ?9-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses. J Biol Chem 289:18707-18
Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L et al. (2014) Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res Bull 109:22-31
Rouse, Michael; Rao, Roshni; Nagarkatti, Mitzi et al. (2014) 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways. J Pharmacol Exp Ther 350:341-52
Rao, Roshni; Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash et al. (2014) Staphylococcal enterotoxin B-induced microRNA-155 targets SOCS1 to promote acute inflammatory lung injury. Infect Immun 82:2971-9

Showing the most recent 10 out of 58 publications