Research in the Beeson group combines biophysical and organic chemistry with cell biology. Our primary focus is the regulation of energy metabolism and cell cycle progression. Specific projects include studies of T-cell activation, myocardial glucose utilization, and redox signaling in tumor cells. Each of the projects involves basic biochemical investigations coupled to the development of therapeutic treatments for pathologic states such as autoimmune diseases, heart disease and cancer. The techniques used include organic synthesis, biophysical spectroscopy, mammalian cell culture, protein biochemistry and microphysiometry. The projects involve collaborations with researchers at the UW School of Medicine, the Fred Hutchinson Cancer Research Center, the Virginia Mason Research Center, and other national and international universities.

T-Cell Activation Helper T cells are activated by peptides complexed to class II proteins of the major histocompatibility complex (MHC II). Although complexes of both foreign- and self-peptides are presented, T-cell responses are usually limited to foreign peptides. Responses to self-peptides cause autoimmune diseases. Studies of peptide-MHC II structure and T-cell signaling have led to the design of modified peptides and peptide mimetics that inactivate T cells specific to the autoantigen involved in a mouse model of Multiple Sclerosis.

Peptide-MHC Structure In addition to the obvious relevance to T-cell activation, the study of peptide-MHC II structure is an interesteing biophysical problem. The peptides are bound to the MHC II proteins with extraordinary kinetic stability- half-times for dissociation in the excess of 200 hrs are common. Crystallographic analyses reveal hydrogen bonding and 'pocket' interactions between peptide and protein. Mutations of these interactions is beginning to reveal a heirarchy among binding interactions similar to the intramolecular interactions that stabilize a protein fold.

Myocardial energy metabolism The adult heart is an 'omnivore' that uses glucose, lipids, and amino acids for energy production. An instrument that continuously measures metabolic fluxes has been developed and it is being used to study the efficiency of heart myoblast glucose oxidation as a function of nutrient and oxygen availability. Therapeutic compounds that minimize heart tissue damage associated with oxygen depravation (i.e., ischemia) are being assayed in this project.

Cancer Cell Biology. Anti-tumor antibodies labeled with radionuclides show considerable promise for the treatment of lymphomas and leukemias. However, the collateral damage to other tissues caused by circulating labeled antibodies is still substantial. An enzyme cleavable labeling technique has been developed and is in pre-clinical evaluation. Compounds that alter tumor cell redox state and, thus, sensitize the cells to radiation induced cell cycle arrest are also being developed.