Development of a mouse model of brown fat dystrophia

棕色脂肪营养不良小鼠模型的建立

• 批准号: 10450253
• 负责人: Juan Sanchez-Gurmaches
• 金额: $ 23.85万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450253
• 关键词: AKT1 gene; AKT2 gene; Address; Adipocytes; Adult; Affect; Age; Bioenergetics; Biology; Biomedical Research; Brown Fat; Cells; Consumption; Data; Development; Disease; Energy Metabolism; FRAP1 gene; Fatty acid glycerol esters; Generations; Genomics; Goals; Growth; Growth Factor; Health; Homeostasis; Human; Institutes; Knock-out; Laboratories; Lead; Medical center; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modeling; Mus; Obesity; Outcome; Pathologic; Pediatric Hospitals; Phosphotransferases; Physiological; Physiology; Positioning Attribute; Potential Energy; Pre-Clinical Model; Production; Regulation; Reporter; Research; Resolution; Resources; Role; Scientist; Signal Transduction; Signaling Molecule; System; Techniques; Testing; Thermogenesis; Tissues; United States National Institutes of Health; adipocyte differentiation; animal model development; base; body system; human model; humanized mouse; in vivo Model; interdisciplinary approach; interest; metabolic phenotype; mouse model; novel therapeutic intervention; obesogenic; pre-clinical research; reproductive; response; virtual

Abstract/Project Summary Mice physiology is deeply affected by brown fat through its control of metabolic homeostasis and production of signaling molecules. However, the vast majority of humans do not have brown fat. This deeply bias the use of mice as a model of human physiology. A mouse model without BAT would allow us to undoubtably determine the putative roles of brown fat in metabolism, in other organ systems and to have a better, humanized, model for preclinical research. Following our mechanistic exploration of the role of growth factors/PI3K/mTOR signaling to understand brown fat formation and metabolism, we unexpectedly generated a mouse model with no discernable classic brown fat, which we call BAT-less mice. The BAT-less mice are born at normal mendelian ratios, fully viable, with normal reproductive capacity and the effects are 100% penetrant. Based on our exciting preliminary data, the central hypothesis for this application is that the complete lack of UCP1 expressing cells in BAT-less mice lead to distinct obesogenic effects compared to UCP1 knockouts. To test this hypothesis, we have developed a toolkit of unique in vivo models including new reporter mouse models and a multidisciplinary approach using whole mouse and tissue-clearing lineage tracing techniques, genomics and state of the art metabolic phenotyping techniques. In Aim 1, we will critically and unequivocally determine if all brown fat depots are lost in BAT-less at all developmental stages using a multi-reporter system tracking UCP1 expressing cells. In Aim 2, we will employ the BAT-less mice to test the contribution of BAT energy consumption to whole body metabolism and obesity propensity independently of UCP1. The BAT-less mice are anticipated to be useful to scientists in an array of fields with implications in multiple NIH institutes. Additionally, the BAT-less mice will be a step forward towards a more humanized, broadly useful, mouse model.

摘要/项目摘要 小鼠的生理机能深受棕色脂肪的影响，通过其控制代谢的稳态和生产 信号分子然而，绝大多数人没有棕色脂肪。这深深地偏向于使用 小鼠作为人类生理学的模型。没有BAT的小鼠模型将使我们能够合理地确定 棕色脂肪在新陈代谢和其他器官系统中的假定作用，并有一个更好的，人性化的模型 用于临床前研究在我们对生长因子/PI 3 K/mTOR作用的机制探索之后 为了了解棕色脂肪的形成和代谢，我们意外地产生了一个小鼠模型， 没有可辨别的典型棕色脂肪，我们称之为无BAT小鼠。没有BAT的小鼠出生时正常， 孟德尔比率，完全可行，具有正常的繁殖能力，效果是100%渗透。基于 根据我们令人兴奋的初步数据，该应用的中心假设是完全缺乏UCP 1， 与UCP 1敲除相比，在无BAT小鼠中表达细胞导致明显的致肥胖效应。测试 根据这一假设，我们开发了一套独特的体内模型，包括新的报告小鼠模型 以及使用整个小鼠和组织清除谱系追踪技术的多学科方法， 和最先进的代谢表型分析技术。在目标1中，我们将严格而明确地确定， 使用多报告系统跟踪，所有棕色脂肪库在所有发育阶段都在BAT-少中丢失 UCP 1表达细胞。在目标2中，我们将使用无BAT小鼠来测试BAT能量的贡献 消费对全身代谢和肥胖倾向的影响独立于UCP 1。没有BAT的老鼠 预计将对一系列领域的科学家有用，并对多个NIH研究所产生影响。此外，本发明还 无BAT小鼠将朝着更人性化、更广泛有用的小鼠模型迈出一步。