The general aim of the proposed research is to examine how certain """"""""exogenous"""""""" and """"""""endogenous"""""""" factors regulate the expression of animal pigments and pigment cells. The approach taken will involve administering allopurinol (a drug used to treat gout in humans) to experimental animals (in this case, axolotls--salamanders) and observing changes that occur in the pigment phenotype. The primary action of allopurinol is to inhibit the enzyme, xanthine dehydrogenase (XDH). It is known from preliminary studies that allopurinol administration to wild type axolotls for periods of from 2-8 weeks results in a gradual darkening of the overall pigment phenotype. During this time, changes occur in the outward appearance of drug-treated animals that apparently involve increasing one pigment cell type (melanophores) accompanied by gradual decreases and eventual disappearance of the other pigment cell types (xanthophores and iridophores). Because the phenotypic changes elicited by allopurinol treatment are identical to the phenotypic characteristics of a genetic mutation in axolotls known as melanoid, it is suspected that these two phenomena are related. Thus, four experimental objectives that are designed to investigate how XDH activity and """"""""melanism"""""""" might be related are proposed: (1) structural studies to follow the fate of the three pigment cell types during drug treatment, (2) quantitative and/or qualitative analyses of purine, pteridine and melanin pigments during drug treatment, (3) analysis of XDH activity during the development of wild type and melanoid axolotls and in drug-treated animals, and (4) administration of allopurinol, purines and pteridines to melanoid axolotls followed by observations of any change in phenotype. Objectives 1-3 are directed toward understanding how XDH activity affects pigment synthesis and, ultimately, pigment cell differentiation. Objective 4 involves a set of preliminary experiments designed to alter and/or correct the melanoid defect.
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