Advancement of the Xiphophorus Model for Studying Disease

项目摘要 剑尾鱼作为长期的生物医学模型，用于多种转化研究。 学科它们被广泛用于与多个NIH任务相关的研究主题 机构/中心。剑尾鱼表现出其他动物模型所不具备的几个特征， 包括高水平的物种间遗传分化，产生物种间杂交的能力， 回交杂种，代表人类疾病的适应性表型。最近完成的基因组 几个剑尾鱼物种的组件，除了剑尾鱼模型的特点，提供了 前提是研究与疾病相关的复杂性状遗传学的无偏见评估， 人类剑尾鱼遗传储备中心（XGSC）的主要目标是保持这些独特的 功能，并保留该模型的优势，用于生物医学研究。XGSC不仅是一个 资源中心托管许多不同的物种，但也是唯一的中心，保存/保持高水平的 易处理的基因型和表型多样性。XGSC拥有61个纯种系，属于24个 剑尾鱼种。它位于得克萨斯州立大学，并积极服务于广泛的研究 社区自1993年以来XGSC具有广泛的国际影响力。我们提供纯种鱼和材料， 来自11个国家的30个实验室的研究人员。在此建议中，我们专注于继续成功 XGSC的运营，加强畜牧业，维护相关资源，并提供 为研究界提供畜牧业培训，为东道机构提供学生培训。 拟议的加强剑尾鱼资源将利用与下列有关的疾病样表型： 癌症、代谢紊乱和人类疾病相关的分子表型。创新，我们 将在细胞、组织和器官水平上研究（a）癌症进展背后的遗传信号 和（B）代谢紊乱/肥胖。我们将通过表征参与这些过程的细胞类型来实现这些目标。 分子水平上的表型，其在驱动疾病进展中起关键作用， 解读疾病发展过程中的表观遗传改变。我们还将（c）表征等位基因， 有助于代谢紊乱的形成。此外，我们会（d）扩大与疾病有关的资源， 通过研究与各种类型的人类疾病相关的分子特征， 其主要目的是鉴定有助于早期疾病诊断和治疗的分子特征。的 实现目标的意义在建议中将是支持继续保持不可替代的 遗传资源和推进我们对分子，细胞和器官水平的理解， 与人类健康和疾病有关的遗传相互作用。提案的结果可以 推进我们对疾病病因的理解，导致新的治疗策略，并确定因果关系或 调节等位基因，可用作个体化药物中的预测因子和靶点。

Project Summary 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 high level of inter-species genetic divergence, capability of producing inter-species hybrids and backcross hybrids, adaptive phenotypes representing human diseases. Recently accomplished genome assemblies for several Xiphophorus species, in addition to the specialties of 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 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 of 11 countries. Herein this proposal, we focus on continuing successful operation of the XGSC, enhancing animal husbandry, maintaining relevant resources, and providing animal husbandry training for the research community, and student training for the host institution. Proposed enhancement of Xiphophorus resources will leverage the disease-like phenotypes related to cancer, metabolic disorders 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) metabolic disorder/obesity. We will achieve theses goal by characterizing cell types involved in these phenotypes on the molecular level which are critically involved in driving disease progression and by deciphering epigenetic alterations during disease development. We will also (c) characterize alleles that contribute to metabolic disorder formation. 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. 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 regulatory alleles that may be utilized as predictors and targets in personalized medicine.