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 棕色脂肪通过控制代谢动态平衡和产生 信号分子。然而，绝大多数人类没有棕色脂肪。这深深地偏向了使用 老鼠是人类生理学的模型。没有蝙蝠的小鼠模型将让我们毫无疑问地确定 棕色脂肪在新陈代谢和其他器官系统中的假定作用，以及有一个更好的、人性化的模型 用于临床前研究。在我们对生长因子/PI3K/mTOR的作用进行机械性探索之后 为了了解棕色脂肪的形成和代谢，我们出人意料地建立了一个小鼠模型 没有可辨别的经典棕色脂肪，我们称之为无蝙蝠老鼠。没有蝙蝠的小鼠在正常情况下出生 孟德尔比例，完全可行，具有正常的生殖能力和效果是100%渗透。基于 我们令人兴奋的初步数据，这一应用的中心假设是完全缺乏UCP1 与UCP1基因敲除相比，在无蝙蝠小鼠中表达细胞导致了明显的肥胖效应。为了测试 在这一假设下，我们开发了一个独特的体内模型工具包，包括新的报告小鼠模型 以及一种使用完整小鼠和组织清除血统追踪技术的多学科方法，基因组学 和最先进的代谢表型技术。在目标1中，我们将批判性和毫不含糊地确定 使用多报告系统跟踪，所有棕色脂肪储存库在所有发育阶段都在无蝙蝠状态下消失 表达UCP1的细胞。在目标2中，我们将使用无蝙蝠的小鼠来测试蝙蝠能量的贡献 消耗对全身代谢和肥胖倾向的影响独立于UCP1。没有蝙蝠的老鼠是 预计将对多个NIH研究所涉及的一系列领域的科学家有用。另外， 没有蝙蝠的小鼠将朝着更人性化、更广泛使用的小鼠模型迈进一步。