3 OVERALL PROGRAM CRITIQUE 3 PROGRESS DURING THE CURRENT FUNDING PERIOD 4 PROGRAM LEADERSHIP 5 PROGRAM AS AN INTEGRATED EFFORT 5 COLLABORATING INSTITUTIONS 6 PROJECT AND CORE SUMMARIES OF DISCUSSION 6 PROTECTION OF HUMAN SUBJECTS 8 VERTEBRATE ANIMALS 9 ADDITIONAL REVIEW CONSIDERATIONS 9 REVISION NOTE Error! Bookmark not defined. SCIENTIFIC REVIEW OFFICER'S NOTES Error! Bookmark not defined. PROJECT 1: Role of HTLV-1 Hbz in Transformation and Disease 10 PROJECT 2: Role of Retroviral Integration Targeting in Cell Transformation 18 PROJECT 3: Effect of HTLV-1 Viral Oncogenes on the Bone Microenvironment in ATL 27 PROJECT 4: Tumorigenic Effects of Tax 35 CORE A: Administration and Biostatistics 43 CORE B: Proteomics and Protein Analysis Core 47 CORE C: Animal Models 50 COMMITTEE BUDGET RECOMMENDATIONS 55 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): The ultimate goal of this Program Project Grant competiting renewal application is to elucidate mechanisms of retrovirus-mediated disease or cellular control events that regulate lymphocyte proliferation/ transformation. A primary common thread among all research groups is the shared use of infectious molecular clones and derivatives of human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2, developed or characterized in our laboratories, and links to established animal models (HIS mice, transgenic mice, rabbits) to test molecular determinants of disease. Each Project Leader brings a unique Project that is interdependent on components of other Projects and Cores in the Program. Project 1 (Green) in collaboration with Project 4 (Ratner) will identify cellular interacting components of both Hbz RNA and protein and will use in vitro and in vivo models to determine the interplay between Hbz and Tax to uncover the mechanisms and pathways necessary for tumor initiation, promotion or maintenance. Project 2 (Kvaratskhelia) in collaboration with Project 1 (Green) and Project 4 (Ratner) will investigate the molecular mechanisms and roles of HTLV-1 integration site selectivity for proviral expression, cell transformation and ultimately pathogenesis. Project 3 (Weilbaecher and Rosol) combines their expertise with Projects 1, 2, and 4 to test the hypothesis that dysregulated tumoral expression of bone turnover factors in Tax and Hbz expressing tumors will reprogram the ATL bone microenvironment towards increased osteoclast resorption and decreased bone formation, which will favor tumor expansion in bone. Project 4 (Ratner) in collaboration with Project 1 will identify and characterize Tax-interactive proteins to determine the mechanism of action of alternative NF?B activation and determine the role of this pathway in Tax-mediated transformation. These four highly integrated Projects are supported by three unique shared resource cores: Core A (Administration and Biostatistics), Core B (Proteomics and Protein Analysis) and Core C (Animal Model Use and Development). For the past 5 years, investigators within this PPG realized robust productivity as demonstrated by 77 peer-reviewed manuscripts;43% collaborative between PPG investigators. This competing renewal PPG assembles and integrates a unique team of physician scientists, basic scientists, lab animal veterinarians, and pathologists and will support interactive basic and translational studies to define transformation mechanisms and therapeutic intervention against HTLV-1 associated leukemia/lymphomas and other related cancers.

Public Health Relevance

Approximately 15-25 million people worldwide are infected with HTLV-1 with a small percentage developing adult T-cell leukemia. The cancer is aggressive and there is currently no effective treatment. The interactive nature of this PPG will provide rationale hypotheses to support translational studies to define therapeutic intervention against retrovirus-induced lymphoma and refine animal models to determine molecular determinants of retrovirus-induced cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA100730-11A1
Application #
8742035
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2014-09-23
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$1,707,225
Indirect Cost
$449,552
Name
Ohio State University
Department
None
Type
Other Domestic Higher Education
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
M Parrula, M Cecilia; Fernandez, Soledad A; Landes, Kristina et al. (2014) Success of measles virotherapy in ATL depends on type I interferon secretion and responsiveness. Virus Res 189:206-13
Dissinger, Nathan; Shkriabai, Nikoloz; Hess, Sonja et al. (2014) Identification and characterization of HTLV-1 HBZ post-translational modifications. PLoS One 9:e112762
Soodgupta, Deepti; Hurchla, Michelle A; Jiang, Majiong et al. (2013) Very late antigen-4 (*(4)*(1) Integrin) targeted PET imaging of multiple myeloma. PLoS One 8:e55841
Yang, Chang; Davis, Jennifer L; Zeng, Rong et al. (2013) Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation. Cancer Discov 3:212-23
Kannian, Priya; Fernandez, Soledad; Jones, Kathryn S et al. (2013) Human T lymphotropic virus type 1 SU residue 195 plays a role in determining the preferential CD4+ T cell immortalization/transformation tropism. J Virol 87:9344-52
Hurchla, M A; Garcia-Gomez, A; Hornick, M C et al. (2013) The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia 27:430-40
Jacob, Aishwarya G; O'Brien, Dennis; Singh, Ravi K et al. (2013) Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma. Neoplasia 15:1049-63
Sharma, Amit; Larue, Ross C; Plumb, Matthew R et al. (2013) BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc Natl Acad Sci U S A 110:12036-41
Kessl, Jacques J; Jena, Nivedita; Koh, Yasuhiro et al. (2012) Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 287:16801-11
Heller, Emanuela; Hurchla, Michelle A; Xiang, Jingyu et al. (2012) Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res 72:897-907

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