The extensive growth of transgenic and gene-targeted mouse models has resulted in an enormous need for mouse pathobiologists that combine strong research training with an extensive understanding of mouse biology and pathology. The Principal investigator's longterm career objectives are to: (1) make seminal contributions to our understanding of oncogene functions in the development and transformation of lymphocytes;(2) provide the highest quality environment and resources for training mouse pathobiologists;and (3) train veterinarians and investigators in the humane care and responsible use of animals in biomedical research. The principal investigator (P.I.) has extensive, high-quality research training in the generation and utilization of transgenic and knockout mice for research in Molecular Immunology and Cancer, as well as veterinary training and experience in laboratory animal medicine. However, the P.l.'s current clinical and administrative responsibilities severely limit the amount of time that the P.I. can be devote to mouse pathobiology research, and to act as a mentor for burgeoning mouse biologists. The purpose of this award application is to provide resources to help relieve the P.I. from administrative and clinical duties so that the P.I can focus on research and training in mouse pathobiology. The broad research objective of the investigative team is to understanding the roles, and mechanism of action, of the Myc oncogene family in the development and transformation of lymphocytes. Myc-family members (c-, N-, and Lmyc) normally function to control cell proliferation, and when deregulated, contribute to the genesis of many types of cancers. However, we still lack a clear understanding as to how Myc normally functions to stimulate cell division.
The specific aims are: (1) To examine the hypothesis that Myc stimulates B lymphocyte development and expansion downstream of the pre-B cell receptor;(2) To examine the hypothesis that Myc stimulates B lymphocyte development and transformation in part by inducing the expression of cyclin D;(3) To examine the hypothesis that Myc amplifies calcium signaling which is important for Myc-induced proliferation and transformation. (4) To examine the hypothesis that Myc directly inhibits the expression of the calcium extrusion pump PMCA4.
These Aims will address our overall hypothesis that Myc stimulates both proliferation and differentiation, in part by stimulating cyclin D expression, and amplifying calcium signaling pathways. Deregulated expression of the myc oncogene is profoundly involved in the genesis of up to 25 percent of a wide-spectrum of cancers in humans. Experiments described in this proposal will utilize transgenic and knockout mice to help elucidate the normal functions of Myc in lymphocyte development, and how deregulated Myc potently stimulates cells to divide in cancer.