EARLY PULMONARY CARCINOGENESIS INDUCED BY JSRV

Colorado State University-Fort Collins, Fort Collins CO

Investigators

Abstract

DESCRIPTION (Applicant's Description): The long-range goal of Nicole Kraipowich, D.V.M., is to become an independent investigator specializing in animal models for human neoplastic disease. The training toward this goal will include mentored research and coursework leading to the Ph.D. in the Department of Pathology at Colorado State University under the guidance of Dr. James C. DeMartini. The applicant's training will involve investigation of ovine pulmonary carcinoma (OPC), a contagious neoplasm induced by jaagsiekte sheep retrovirus (JSRV) morphologically similar to human bronchioloalveolar carcinoma, a tumor only weakly associated with smoking. To elucidate the role of JSRV in the early oncogenesis of OPC, proposed studies will focus on the initial events that occur after JSRV infection, including identification of target cells for viral infection and proliferation, determination of clonality of proliferating pneumocytes, and in vivo evaluation of proliferative effects o f viral gene products. The central hypothesis is that polyclonal proliferation of alveolar type II cells, Clara cells, or a common progenitor cell is induced by viral gene products. To address this hypothesis, three specific aims will guide our work: (1) To identify the initial pulmonary cell types infected by JSRV. Newborn lambs will be infected with JSRV constructs containing a marker gene and lung cell-specific mRNA probes will be used to identify the target cells for infection. (2) To examine the clonality and identity of proliferating pulmonary epithelial cells and their JSRV infection status. Proliferation will be assayed by nucleotide analogue incorporation and clonality assessed by Southern blot hybridization of lung tumor DNA using JSRV probes. (3) To examine the capacity of JSRV proteins to induce pulmonary epithelial cell proliferaton in vivo. JSRV vectors containing viral gag/pol, orf X and env sequences will be introduced into lambs and lung cell proliferation assessed. The results of these studies will assist in understanding the mechanisms of initiation and progression in this unique model of pulmonary carcinogenesis and may lead to novel strategies for early detection and even prevention of human lung cancer.