We seek to continue the productive interactions of Project 5 in P01 CA100730 by examining the role of innate and adaptive immunity in the initiation and maintenance of HTLV-1 Tax-mediated lymphoma. A variety of animal models and clinical reports support the role of inflammatory mediators in the promotion of cancer, yet the molecular links between inflammation and cancer are incompletely understood. Inflammatory mediators and viral factors that promote cell proliferation are intimately linked in HTLV-1-induced carcinogenesis and have been a long-term interest of Dr. Ratner (Project 5). The PPG investigators have extensively collaborated using molecular clones and animal models to provide fundamental information about the pathogenesis of the viral infection and mechanisms of ATL including the development of novel transgenic mouse models that have demonstrated the role of NFicB in cancer development. In the proposed Project 5, we will extend his model to test the role of inflammation in novel T cell lymphoma models. Adult T cell leukemia / lymphoma (ATL), caused by HTLV-1, is an aggressive T cell malignancy driven primarily by NFxB signaling pathways. The model systems chosen are transgenic mouse models of HTLV-1 Tax, which results in the development of lymphoma in a microenvironment of inflammatory cells. The role of neutrophils in the innate immune system will be examined in Aim 2 using myeloperoxidase knockout mice. The role of T cells in the adaptive immune system will be examined in Aims 1 and 3, using T cell receptor activation or mitogen and/or miRNA (HBZ) induction of T cell proliferation.
The Specific Aims of the Project are: 1) Test T Cell activation in Tax tumorigenesis by utilizing T-cell receptor (TCR) transgenic and Tax transgenic mice to examine the contributions of innate and adaptive immunity to initiation and maintenance of tumors, 2) Test neutrophil activation in Tax-mediated tumorigenesis by examining neutrophil activation in inflammatory lesions and tumors in myeloperoxidase knockout mice, and 3) Determine the combined Influence of T cell activation and inflammation by examining the role of a novel anti-sense encoded viral miRNA (HBZ) that activates T-cells and contributes to HTLV-1-mediated tumorigenesis. These highly collaborative studies will provide new insights into molecular and cellular pathways that are critical to a wide variety of malignancies and offer insight into beneficial intervention strategies against cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA100730-10
Application #
8376223
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$404,581
Indirect Cost
$103,444
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Murali, Bhavna; Ren, Qihao; Luo, Xianmin et al. (2018) Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss. Cancer Res 78:5618-5630
Huey, Devra D; Niewiesk, Stefan (2018) Production of Humanized Mice through Stem Cell Transfer. Curr Protoc Mouse Biol 8:17-27
Romeo, Megan; Hutchison, Tetiana; Malu, Aditi et al. (2018) The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis. Virology 518:103-115
Cherian, Mathew A; Olson, Sydney; Sundaramoorthi, Hemalatha et al. (2018) An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia. J Biol Chem 293:6844-6858
Huey, Devra D; Bolon, Brad; La Perle, Krista M D et al. (2018) Role of Wild-type and Recombinant Human T-cell Leukemia Viruses in Lymphoproliferative Disease in Humanized NSG Mice. Comp Med 68:4-14
Pérès, Eléonore; Blin, Juliana; Ricci, Emiliano P et al. (2018) PDZ domain-binding motif of Tax sustains T-cell proliferation in HTLV-1-infected humanized mice. PLoS Pathog 14:e1006933
Panfil, Amanda R; Al-Saleem, Jacob; Howard, Cory M et al. (2018) Stability of the HTLV-1 Antisense-Derived Protein, HBZ, Is Regulated by the E3 Ubiquitin-Protein Ligase, UBR5. Front Microbiol 9:80
Kenney, Adam D; Dowdle, James A; Bozzacco, Leonia et al. (2017) Human Genetic Determinants of Viral Diseases. Annu Rev Genet 51:241-263
Webb, Lindsay M; Amici, Stephanie A; Jablonski, Kyle A et al. (2017) PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis. J Immunol 198:1439-1451
Singh, Gatikrushna; Fritz, Sarah M; Ranji, Arnaz et al. (2017) Isolation of Cognate RNA-protein Complexes from Cells Using Oligonucleotide-directed Elution. J Vis Exp :

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