I have studied signal transduction in lymphocytes for more than 30 years, with a recent focused interest in the role of cytoplasmic tyrosine kinases and transmembrane phosphatases, molecules critically important in normal lymphocyte responses to pathogens and in responses to tumors. Mutations of some of these molecules within the hematopoietic lineage can lead to malignant transformation. I have studied the influence of dysregulation of tyrosine kinases, particularly of ZAP-70, and phosphatases such as CD45 and CD148 in mouse models of lymphoproliferation, a frequent precursor of malignant transformation. My lab discovered ZAP-70, demonstrated its importance in T cell antigen receptor signaling, and was one of the first to report ZAP-70 mutations as a cause of human SCID. We have also collaborated with Tom Kipps (UCSD) on the expression of ZAP-70 in human Chronic Lymphocytic Leukemia (CLL) as a prognostic marker and have studied its role in CLL cells. We have established several mouse models of ZAP-70, Csk, and CD45 mutant alleles to understand the consequences of these alleles on lymphocyte signaling.
During my career, I have served on the Scientific Advisory Boards of several biotechnology companies. Two have successful FDA-approved therapies for malignancies. Sunitinib, whose early development occurred at Sugen and then at Pfizer, has been approved for renal cell carcinoma, gastrointestinal stromal tumors, and neuroendocrine pancreatic tumors. Plexxikon developed Vemurafinib, a pioneering targeted therapeutic for melanomas harboring the BRAF V600E mutation, which occurs in approximately half of melanoma patients. I am a cofounder of Nurix, Inc., which seeks to develop therapeutics for various malignancies by targeting ubiquitin ligases.
May 18, 2020 - June 30, 2021 - Defining the Unique Properties of the Distinct Signaling Machinery Used by the TCR, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: P01AI091580
July 1, 1978 - June 30, 2021 - Medical Scientist Training Program, Co-Principal Investigator. Sponsor: NIH/NIGMS, Sponsor Award ID: T32GM007618
December 8, 2015 - November 30, 2020 - The cell and molecular mechanisms underlying CD28 costimulation, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R37AI114575
December 8, 2015 - November 30, 2020 - The cell and molecular mechanisms underlying CD28 costimulation, Principal Investigator. Sponsor: NIH/NIAID, Sponsor Award ID: R01AI114575
University of Chicago, Chicago, IL, Ph.D., 1978, Immunology
University of Chicago, Chicago, IL, M.D., 1979, Medicine