National Institutes of Health - National Cancer Institute Funded Program Project Grant

Retrovirus Models of Lymphocyte Transformation & Disease
Michael Lairmore, DVM, PhD Principal Investigator

An investigative team of Center for Retrovirus Research faculty has been awarded a $9.8 million grant from the National Cancer Institute to investigate retroviral models of cancer. The focus of this Program Project Grant (PPG) is use of integrated retrovirus models to understand basic cellular mechanisms of cancer. The research team will work together and exploit their established retroviral models to study fundamental mechanisms of cell biology with the ultimate goal of new approaches to cancer therapy.

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 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. These findings will support efforts to further discover new therapeutic targets against retroviral-induced lymphoma and its paraneoplastic syndromes (e.g., hypercalcemia and bone resorbtion). Each project within this PPG application shares the overall common goal to elucidate mechanisms of retrovirus-mediated disease.

The components: 5 Integrated projects, 3 cores

In Project 1, Dr. Lairmore will investigate the essential role of the novel accessory proteins of human T-lymphotropic virus type 1 (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 seeks to understand the essential role of p12I and p30II in transcriptional regulation in T-lymphocytes and in the establishment of HTLV-1 infection in vivo.

In Project 2, Dr. Patrick Green will characterize a novel function of HTLV-1 and HTLV-2 related accessory gene products that act post-transcriptionally as negative regulators of both Tax and Rex. The goals are to define the post-transcriptional mechanisms of p28/p30 repressive activity by identifying and characterizing functional domains and biochemical properties of p28, determining the primary sequence and structure/function of the p28 mRNA target, and determining the contribution of p28 in viral replication, lymphocyte activation/transformation, and persistence of the virus and in vivo. Understanding the exact mechanism of action of post-transcriptional control of p28/p30 ultimately will provide a means for therapeutic targeting of these proteins to eradicate HTLV persistence in the host. Important to this PPG, our findings will contribute to understand how HTLV alters T-cell physiology and thus gain insight into the mechanisms of regulating viral replication and the early phases of lymphocyte activation and cellular transformation.

In Project 3, Dr. Kathleen Boris-Lawrie, will investigate the novel retroviral translational enhancer in spleen necrosis virus that commandeers host cell proteins to control viral protein synthesis in T cells. This project will test post-transcriptional control of retrovirus cell interaction through the use of novel control elements and retroviral vectors. This fundamental knowledge will then be applied to engineer enhanced retroviral vectors systems for gene transfer applications.

In Project 4, Dr. Thomas Rosol will evaluate molecular determinants of hormonal-induced hypercalcemia, an important complication of viral-associated cancer. This project defines the role and regulation of parathyroid hormone related protein in ATL and its associated paraneoplastic syndrome, humoral hypercalcemia of malignancy in human and animal models.

Project 5 is directed by Drs. Lee Ratner and Katherine Weilbaecher of Washington University, St. Louis, Missouri. This project continues the productive collaboration between The Ohio State University and Washington University, St. Louis to determine the role of the regulatory protein Tax in lymphocyte proliferation and virus-associated disease in a transgenic mouse cancer model.

Three Core Facilities facilitate integration at administrative and scientific levels. The Adminstrative/Biostatics Core A , which is directed by Dr. Lairmore is responsible for maximizing integration between the PPG projects and providing the optimum statistical analysis for each of the Projects. The Imaging Core B , which is directed by Dr. Lawrence Mathes provides state-of-the-art confocal and IVIS imaging instrumentation that is used by all of the investigators. The Animal Core C , which is directed by Dr. Stefan Niewiesk provides animal models systems of retrovirus-induced malignancy.

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 recently funded program project grant is a visible product of the Center for Retrovirus Research, which originated and is administered in the College of Veterinary Medicine.