and Specific Aims.) This project will examine several aspects of senescent cell antigen (SCA). SCA is a molecule, originally described by the investigator, which may be involved in targeting aged cells for removal or destruction. SCA is a degradation or cleavage product of an anion transport molecule - band 3. This cleavage takes place in a two-step fashion, resulting in the revelation of a cryptic determinant recognized by naturally occurring IgG autoantibodies. The coating of cells with anti-SCA apparently targets these cells for destruction or removal via phagocytic processes. While originally described in erythrocytes, the SCA appears to be present on many cell types, and has recently been implicated in several syndromes associated with aging per se or abnormalities in the aging process (e.g.; Alzheimer's disease). This application lists five major aims. 1) Develop recombinant antibodies to SCA in order to pursue subsequent mechanistic studies. This will be approached through the generation of EBV-transformed lines and construction of recombinant heavy light chain single molecules by molecular techniques. 2) Complete mapping of the antigenic sites on Band 3 in relation to the sites important for anion transport. 3) Develop a synthetic aging antigen through 'designer' peptide approaches that inhibits binding of naturally occurring SCA-specific antibodies better than does the native molecule. 4) Define molecular changes that occur during aging which initiate changes in the band 3 molecule. 5) Identify enzymes responsible for the degradation of band 3.
