An investigative team of Center for Retrovirus Research faculty has been awarded a $10.9 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.
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 desorption). Each project within this PPG program shares the overall common goal to elucidate mechanisms of retrovirus-mediated disease.
In Project 1, Dr. Stefan Niewiesk and Dr. Mumaka Kvaratskhelia 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 role of p30 and its mutants in DNA damage signaling, cell cycle progression, DNA repair, and integration, along with testing the amino acids of p30 for their role in HTLV-1 infection.
In Project 2, Dr. Patrick Green will define novel post-transcriptional mechanisms of HTLV by studying the structure/function motifs of p28 and determine the contribution of p28 to viral replication and cellular transformation.
In Project 3, Dr. Kathleen Boris-Lawrie will investigate the fundamental translational control mechanisms in both retroviruses and in crucial growth control genes by studying the RHA gene expression and cytoplasmic localization during cell cycle progression, along with characterizing the regulation of RHA translational control.
In Project 4, Drs. Katherine Weilbaecher of Washington University and Thomas Rosol of Ohio State University will combine their expertise to study the role of bone microenvironment in osteolytic and osteoblastic tumor models by investigating the regulation and function of PTHrP in ATLL cells.
Project 5 is directed by Dr. Lee Ratner of Washington University, St. Louis, Missouri. This project continues the productive collaboration between The Ohio State University and Washington University, St. Louis to test the contribution of the inflammatory microenvironment in carcinogenesis using unique transgenic mouse models.
Three Core Facilities facilitate integration at administrative and scientific levels. The Adminstrative/Biostatics Core A , which is directed by Dr. Green is responsible for maximizing integration between the PPG projects and providing the optimum statistical analysis for each of the Projects. The Imaging and Proteomics Core, which is directed by Drs. Lawrence Mathes and Mamuka Kvarastkhelia 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 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.