Animal Metabolism Phenotyping Core

动物代谢表型核心

• 批准号: 8666631
• 负责人: DANIEL POMP
• 金额: $ 3.29万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8666631
• 关键词: Adopted; Age; Amino Acids; Animal Model; Animals; Arts; Atherosclerosis; Biological; Biological Models; Biomedical Research; Body Weight; Body fat; Collection; Communities; Consomic Strain; Contracts; Core Facility; Data; Development; Diabetes Mellitus; Diet; Disease; Disease susceptibility; Energy Intake; Energy Metabolism; Equipment; Exercise; Experimental Designs; Food; Food Preferences; Funding; Gender; Genetic; Genetic Engineering; Genetic Medicine; Genome; Genotype; Goals; Health Services Accessibility; Home environment; Housing; Human; Hypertension; Inbred Mouse; Inbred Strain; Inbreeding; Individual; Institutes; International; Malignant Neoplasms; Measurement; Measures; Mental disorders; Metabolic; Metabolism; Methods; Modeling; Mus; Mutant Strains Mice; Names; National Center for Research Resources; Nobel Prize; Nutritional; Obesity; Pharmacy facility; Phenotype; Physiological; Pilot Projects; Play; Population; Process; Proxy; Public Health; Quality Control; Randomized; Recombinants; Reproduction; Research; Research Personnel; Research Project Grants; Resources; Role; Science; Scientist; Services; Site; System; Time; Tissues; United States National Institutes of Health; Variant; base; bone mass; congenic; cost efficient; diet and exercise; drinking; energy balance; genome-wide; glucose metabolism; knockout gene; medical schools; member; microbiome; mouse model; mutant; nutrition; nutritional genomics; overexpression; repository; research facility; trait

Over the past century, the mouse has become the premier mammalian model system for biomedical research, particularly for nutrition and obesity research (Pomp et al., 2008). Scientists from nearly all biomedical fields have adopted the mouse as a model organism because of its close genetic and physiological similarities to humans, the ability to evaluate large populations, and the ease with which its genome can be manipulated and analyzed. Like humans, mice naturally develop (or can be induced to develop) diseases including obesity, diabetes, atherosclerosis, hypertension and cancer. The mouse models currently available for biomedical research include hundreds of unique inbred strains, each with their own relatively well defined disease susceptibilities, and various crosses, congenics, chromosome substitution strains and recombinant inbred lines derived from these inbred strains (Peters et al, 2007). There are thousands of genetically engineered mutants ranging from overexpression models to gene knockouts to more specialized models with targeted amino acid changes and tissue specific expression that exist to study specific contributions to disease systems and processes. Energy balance, the relationship between energy consumed (through food and drink), and energy expended (through activity and metabolic rate) play a central role in many diseases, including obesity, diabetes, athelerosclerosis, reproduction, certain cancers and some psychiatric disorders, to name few. While mouse models are important in facilitating research on the impacts of genetics, nutrition and their interaction on energy balance, the overall utility of these models is often limited due to relatively basic Phenotyping capabilities. For example, many studies on obesity in mice continue to use body weight as a proxy for body fat, despite the fact that the correlation between these two traits is only -50% and can vary significantly based on genotype, gender, age. diet and exercise level (Eisen and Prasetyo, 1988). Perhaps more importantly, metabolic consequences of nutritional treatments and disease often remain the focus of speculation because the ability to "drill down" for accurate measures of components of energy expenditure and energy intake remain outside the scope of most researchers due to expense and technological difficulties. Our long-term objective is to facilitate multifaceted use of mouse models to study energy balance by supporting high quality and high throughput phenotyping of energy balance components, including energy intake, food preference, metabolic rate, home cage activity, voluntary exercise, glucose metabolism, gut microbiome characterization, and serial measurements of body fat, lean mass and bone. Towards this goal, the UNC NORC created the Animal Metabolism Phenotyping (AMP) Core Facility to provide high quality, high throughput and full-service energy balance phenotyping services to a broad array of NIH-funded biomedical researchers from across the UNC campus, including the Schools of Medicine, Public Health, Arts and Sciences and Pharmacy. Building on the legacy of Nobel Prize winner Dr. Oliver Smithies, UNC has made a major commitment to research using mouse models, culminating in the recent completion of a Vivarium, located in the new UNC Genetic Medicine Building (GMB), that has the capacity for housing approximately 45,000 mouse cages, making it one of the largest mouse research facilities in the US. In addition to housing one site of the AMP core as well as mice from many investigators across campus, the GMB Vivarium is the home to two major international research resources. The first is the National Center for Research Resources (NCRR) funded Mouse Mutant Regional Resource Centers, which acts as a repository for mutant strains of mice. The second is a unique and powerful emerging mouse population called the Collaborative Cross (CC), whose development and use has been funded by several diverse NIH institutes. The CC is a large panel of recombinant inbred mouse lines created from an 8-way cross of inbred strains (Churchill et al., 2004), and is the only mammalian resource that has high and uniform genome-wide variation effectively randomized across a large, heterogeneous, and reproducible population which also supports integration across environmental and biological conditions, across genotypes, across diets, and over time (Chesler et al., 2008). Unique to UNC's NORC, the AMP core will provide full service access to the CC for nutrition and nutrigenomic oriented research, providing targeted and focused opportunities for pilot projects and collection of preliminary data to be used for full proposals based on this unprecedented resource.

在过去的一个世纪中，小鼠已成为生物医学研究的主要哺乳动物模型系统，特别是营养和肥胖研究（Pomp 等，2008）。几乎所有生物医学领域的科学家都采用小鼠作为模式生物，因为它与人类在遗传和生理上非常相似，能够评估大量群体，并且可以轻松地操纵和分析其基因组。与人类一样，小鼠自然会患上（或可以诱导患上）疾病，包括肥胖、糖尿病、动脉粥样硬化、高血压和癌症。目前可用于生物医学研究的小鼠模型包括数百种独特的近交系，每种都有自己相对明确的疾病易感性，以及源自这些近交系的各种杂交、同类、染色体取代系和重组自交系（Peters等，2007） 。有数千种基因工程突变体，从过度表达模型到基因敲除，再到具有目标氨基酸变化和组织特异性表达的更专门的模型，这些模型的存在是为了研究对疾病系统和过程的特定贡献。 能量平衡，即能量消耗（通过食物和饮料）与能量消耗（通过活动和代谢率）之间的关系，在许多疾病中发挥着核心作用，包括肥胖、糖尿病、动脉粥样硬化、生殖、某些癌症和一些精神疾病，举几个例子。虽然小鼠模型对于促进遗传学、营养及其相互作用对能量平衡的影响的研究很重要，但由于相对基本的表型分析能力，这些模型的整体效用往往受到限制。例如，许多关于小鼠肥胖的研究继续使用体重作为体脂的代表，尽管事实上这两个特征之间的相关性仅为-50%，并且可能因基因型、性别、年龄而存在显着差异。饮食和运动水平（Eisen 和 Prasetyo，1988）。也许更重要的是，营养治疗和疾病的代谢后果常常仍然是猜测的焦点，因为由于费用和技术困难，“深入研究”能量消耗和能量摄入成分的准确测量的能力仍然超出了大多数研究人员的范围。 我们的长期目标是通过支持能量平衡组成部分的高质量和高通量表型分析，促进多方面使用小鼠模型来研究能量平衡，包括能量摄入、食物偏好、代谢率、笼内活动、自愿运动、葡萄糖代谢、肠道微生物组特征，以及身体脂肪、去脂体重和骨骼的连续测量。为了实现这一目标，UNC NORC 创建了动物代谢表型 (AMP) 核心设施，为来自 UNC 校园（包括医学院、公共卫生学院）的众多 NIH 资助的生物医学研究人员提供高质量、高通量和全方位服务的能量平衡表型服务、艺术与科学以及药学。 在诺贝尔奖获得者 Oliver Smithies 博士的遗产基础上，北卡罗来纳大学做出了重大承诺，利用小鼠模型进行研究，最终在新的北卡罗来纳大学遗传医学大楼 (GMB) 内建成了一个饲养室，该大楼可容纳容纳约 45,000 个小鼠笼子，使其成为美国最大的小鼠研究设施之一。除了容纳 AMP 核心的一个站点以及校园内许多研究人员的小鼠外，GMB 动物园还是两个主要国际研究资源的所在地。第一个是国家研究资源中心 (NCRR) 资助的小鼠突变体区域资源中心，该中心充当小鼠突变体品系的储存库。第二种是一种独特而强大的新兴小鼠群体，称为“协作交叉”(CC)，其开发和使用由多个不同的 NIH 研究所资助。 CC 是由自交系 8 路杂交创建的一大组重组自交系小鼠品系（Churchill 等，2004），并且是唯一具有高度一致的基因组范围变异的哺乳动物资源，该变异有效地随机分布在大范围内。 、异质性和可再生的群体，也支持跨环境和生物条件、跨基因型、跨饮食和随着时间的推移进行整合（Chesler et al., 2008）。 AMP 核心是北卡罗来纳大学 NORC 的独特之处，将为营养和营养基因组学研究提供进入 CC 的全面服务，为试点项目和收集初步数据提供有针对性和重点的机会，以用于基于这一前所未有的资源的全面提案。