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Xiphophorus fishes serve as long-standing biomedical models for translational research in multiple disciplines. They are used widely in research topics that connect to the missions of multiple NIH Institutions/Centers. Xiphophorus fish exhibit several features that no other animal model shares, including a high level of inter-species genetic divergence, capability of producing inter-species hybrids and backcross hybrids, and adaptive phenotypes representing human diseases. Recently accomplished genome assemblies for several Xiphophorus species, in addition to the specialties of the Xiphophorus model, provide the premise to study non-biased assessment of genetics underlying complex traits associated with diseases in humans. The primary goal of the Xiphophorus Genetic Stock Center (XGSC) is to maintain these unique features and preserve the strength of this model to be used in biomedical research. The XGSC is not only a resource center hosting many different species, but also the only center that preserves/maintains a high level of tractable genotypic and phenotypic diversity. The XGSC maintains 61 pedigreed lines that belong to 24 Xiphophorus species. It resides at Texas State University and has actively served a broad research community since 1993. XGSC has a wide international impact. We provide pedigreed fish and material to investigators in 30 laboratories from 11 countries. Herein this proposal, we focus on continuing successful operation of the XGSC, enhancing animal husbandry, maintaining relevant resources, providing animal husbandry training for the research community, and student training for the host institution. Proposed enhancement of Xiphophorusresources will leverage the disease-like phenotypes related to cancer, obesity and the human disease-associated molecular phenotypes. Innovatively, we will investigate on the cellular, tissue and organ level the genetic signaling underlying (a) cancer progression and (b) development of obesity. We will achieve these goals by characterizing cell types involved in these phenotypes on the molecular level which are critically involved in driving disease progression. In addition, we will decipher epigenetic alterations during disease development. We will also (c) characterize alleles that contribute to natural and diet-induced obesity. In addition, we will (d) expand disease related resources of Xiphophorus by studying molecular traits that are associated with various types of human diseases, with a primary goal of identifying molecular traits that can benefit early disease diagnosis and treatment. By completing the proposal, we will additionally establish Xiphophorus resources that include a cell type atlas, disease associated methylome, and organ-specific disease-associated dysregulated genes. The significance of achieving the goals in the proposal will be the support to continue to maintain irreplaceable genetic resources and advancing our understanding on the molecular, cellular and organismic level of genetic interactions associated with human health and diseases. The outcomes of the proposal can forward our understanding of disease etiology, lead to novel therapeutic strategies, and identify causal or modulatory alleles that may be utilized as predictors and targets in personalized medicine.