The objectives of this proposal are to isolate, characterize, and clone the receptor for interferon gamma (IFN-gamma). The overall goals are to determine the structure and functions of the receptor for IFN-gamma and the components coupling the receptors to its biological actions. Knowledge of its structure and transducing elements may ultimately permit targeting the receptors or by-passing them with small non-protein molecules. The following represent specific aims: 1. Isolation, purification and characterization of the IFN-gamma receptor. 2. Preparation of poly- and monoclonal antibodies to the IFN-gamma receptor. 3. Genetic analysis of the human and mouse IFN-gamma receptors and factors linking the receptor to specific functions. 4. Identification and characterization of cDNA and genomic clones encoding the IFN-gamma receptor. 5. Expression and production of receptors and transducers in Escherichia coli and in animal cells. 6. Interferon receptors: biological studies; role in differentiation, development and disease. Mouse and hamster cells containing human DNA in cosmid or in phage vectors will be used to select cells responding to human IFN-gamma through selection by use of histocompatability antigen surface markers. The human DNA will be isolated from these cells by rescue or screening techniques. DNA from the isolated clones will be mapped and sequenced. Expression in heterologous animal cells will be used to delineate the linkage of the receptor to the signal transducing elements. Antibodies to the receptors and DNA clones encoding the receptors will be used to study directly their modulation under various physiological and pathological circumstances. Since IFN-gamma and other interferons are in use as therapeutic agents for the treatment of malignancy and other diseases, it is essential to understand how they interact with cells. Knowledge of this phenomenon should expedite its therapeutic uses and provide a basis for developing improved strategies for the treatment of diseases with IFN-gamma alone or in combination with other genes.
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