Arginine vasopressin (AVP) is a neuroendocrine hormone that can positively regulate the production of lymphokines such as gamma interferon (IFNgamma), which is evidence that it is a biological response modifier. As such, it has potential in host defense against cancer, including cancer of the brain where AVP and its receptor are present as well as cells capable of producing classic biological response modifiers. The objective of this proposal is to determine the mechanism by which AVP positively regulates IFNgamma production at level of ligand-receptor interaction. This will involve isolation and characterization of the AVP receptor on lymphocytes and modulation of AVP action at the receptor level by novel AVP-binding peptides. We plan to achieve the objective by: (1) Further determination of the structural basis by which AVP-binding peptides convert AVP into an antagonist of its own action at the level of peptide-peptide interaction and receptor interaction. (2) Determine if antibodies that specifically block AVP function do so by binding to the AVP receptor. (3) Use antibodies to AVP-binding peptides (antireceptor?) to affinity purify AVP receptor. This will allow for subsequent production of antibodies that are capable of recognizing a variety of antigenic determinants on the AVP receptor which is important in receptor detection. (4) Use AVP anti-receptor antibodies to identify cells in the spleen that express receptor and to screen various cell lines for receptor expression and modulation. (5) Sequence the affinity purified AVP receptor. (6) Extend AVP-binding peptide studies to modulation of AVP vasopressor and antidiuretic activities as these receptors are perhaps structurally related but functionally different from the lymphocyte receptor as assessed by agonists and antagonists of AVP. The proposed studies are important in that they deal with the dynamics of the structural aspects of AVP and its receptor that may determine the conditions under which neuropeptides such as AVP function in pleiotropic fashion as agonists or antagonists, particularly as biological response modifiers. The studies also result in the development of the reagents and tools for the ultimate cloning of the AVP receptor.
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