National Institutes of Health - National Cancer Institute Funded Program Project Grant
Retrovirus Models of Cancer
Patrick Green, PhD Principal Investigator
An investigative team of Center for Retrovirus Research faculty has been awarded a $8.6 million program project grant (PPG) from the National Cancer Institute to investigate retroviral models of cancer (2014-2019). The ultimate goal of this PPG is to utilize the human T-cell leukemia virus type 1 (HTLV-1) T-cell immortalization model and the humanized immune system (HIS) mice or Tax transgenic mice to gain an understanding of how microenvironmental, cellular, and viral factors cooperate to promote development of cancer, and with this knowledge, to identify unique targets for diagnosis and treatment of HTLV-1 infection and adult T-cell leukemia and related leukemia/lymphoma.
Purpose: mechanisms of retrovirus-mediated disease
The PPG is designed to foster synergistic interactions between the laboratories and characterize mechanisms that define retroviral exploitation of the cellular environment during HTLV-1 replication and disease progression. Concurrently each laboratory has key interrelated goals to define events that control the transition of lymphocytes from activation through immortalization and transformation. The specific aims are:
Aim 1: Determine how HTLV-1 oncogene expression (hbz and tax) and preferential activation of the alternative NFkB signaling pathway work in concert to promote optimal proviral gene expression, T-cell immortalization and transition to adult T-cell leukemia (ATL).
Aim 2: Determine the mechanism by which the microenvironment and microenvironmental factors sustain HTLV-1 immortalized T-cells and support progression to ATL. Further, to determine how these cells contribute to paraneoplastic disease syndromes.
Aim 3: Discover new therapeutic targets against retrovirus infections, retroviral-induced lymphoma and their paraneoplastic disease syndromes.
The components: 3 integrated projects, 3 cores
In Project 1, Dr. Patrick Green will investigate the essential role and cooperativity of the Hbz and Tax proteins of HTLV-1, the first described human retrovirus. This retrovirus is the cause of an aggressive form of lymphoma and leukemia, as well as a number of immune system disorders. This project will directly determine if and how Hbz RNA and/or the HBZ protein alone or in combination with Tax, contribute to the long term survival of HTLV-1-infected T-cells and their eventual neoplastic transformation. Dr. Lee Ratner (Project 2) will contribute to the in vivo Tax/Hbz component of Project 1.
Project 2 is led by Dr. Lee Ratner of Washington University, St. Louis, Missouri and in collaboration with Dr. Patrick Green (Project 1) hypothesize that Tax activation of NFκB is critical for tumorigenesis, particularly the alternative NFκB pathway. This project will test this hypothesis, and identify and characterize Tax-interactive proteins that mediate alternative NFκB activation.
In Project 3, Drs. Thomas Rosol of Ohio State University and Katherine Weilbaecher of Washington University will combine their expertise and will focus on how bone microenvironment, in particular the hedgehog (HH) and Wnt pathways, contributes to ATL development and progression. This work takes into consideration not only the extrinsic factors in the bone microenvironment but also how the microenvironment influences, or is influenced by Tax and Hbz signal transduction.
Three support Cores facilitate the integration at administrative and scientific levels. The Adminstrative/Biostatics Core A , which is directed by Dr. Patrick Green is responsible for maximizing integration between the PPG projects and providing the optimum statistical analysis (Dr. Soledad Fernandez) for each of the Projects. The Proteomics and Protein Analysis Core, which is directed by Dr. Mamuka Kvarastkhelia supports all the projects and utilizes state-of-the-art equipment/techniques including MS-based proteomics, AKTA-fast protein liquid chromatography (obtaining purified recombinant proteins), and an EnSpire multimode plate reader (monitoring protein-protein and protein-nucleic acid interactions. The Animal Core C , which is directed by Dr. Stefan Niewiesk provides animal models systems of HTLV-1-induced malignancy. These include rabbit model of HTLV-1 infection, transgenic mouse models of tumorigenesis, transplantation leukemia models in immune deficient mice.
Program Project Grants encourage interdisciplinary research
Program project grants represent an important maturation of the research mission of the College of Veterinary Medicine. Historically, the National Institutes of Health has relied on multi-component awards, such as program projects, to encourage multidisciplinary collaboration in areas requiring integration and central direction of basic and clinical research components. Program projects and center grants have a well-defined central theme, include extensive shared resources or core facilities, and are led by a principal investigator who has the authority and responsibility to manage the overall research effort and budget. Typically a program project group consists of a set of investigator-initiated applications for independent research on related topics, with a formalized agreement to collaborate in specific ways to enhance the achievement of the goals of all of the projects. Other benefits of the program include the establishment of collaborations on an equal footing at separate sites and fostering formal collaborations between multiple institutions. The funded program project grant (years 11-15) is a visible product of the Center for Retrovirus Research, which originated and is administered in the College of Veterinary Medicine.