There is an increasing call for alternative animal models as surrogates for assessing risks to human health. The see-through medaka is a unique animal model, which we believe has enormous potential for assessing such risks. This animal model is transparent in embryonic, juvenile and adult life stages with principal internal organs visible through the body wall in the living animals. With the see-through medaka, ease of phenotypic analysis currently available in existing alternative models during embryogenesis may now be extended to later life stages. Structural and functional changes at molecular, cellular, tissue and organ/system levels may be imaged non-invasively leading to greatly enhanced phenotypic characterization throughout life.
Four specific aims are proposed: 1) Define medaka liver growth and development emphasizing relationship of hepatic tubules to microvasculature. 2) Image hepatocyte and biliary epithelial cell interaction in bile formation within the hepatic tubule. 3) Construct cell type specific transgenic see-through medaka to extend noninvasive detection of liver development/remodeling and growth. 4) To produce verified hepatic injury in larval see-through medaka by exposure to a reference hepatotoxin known to target intrahepatic biliary function, and, in separate individuals, to a known carcinogen that results in degenerative and neoplastic lesions in medaka liver. The compressed life cycle of the medaka, when coupled with its transparent features, makes this model particularly well suited to study post-embryonic development, aging, toxicity, mutagenesis and carcinogenesis. Particularly important is a model for evaluating manifestations of early life stage exposure where initial molecular derangement may be separated from adult dysfunction by long intervals. Effort in the proposed research will focus on processes to extend noninvasive detection of liver development/remodeling and growth. We have chosen to study the liver because of our extensive knowledge with this organ system and it's importance in: uptake, metabolism, storage and redistribution of nutrients and other endogenous molecules, metabolism of xenobiotics, and formation and excretion of bile. Thus, in this application, we will establish specific molecular imaging technologies to study organ system growth and development and to enhance this model's potential to study effects of human disease.
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