Development of a mouse model of brown fat dystrophia

棕色脂肪营养不良小鼠模型的建立

基本信息

批准号：
10590670
负责人：
Juan Sanchez-Gurmaches
金额：
$ 19.88万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/10590670
关键词：
AKT1 gene AKT2 gene Address Adipocytes Adult Affect Age Bioenergetics Biology Biomedical Research Brown Fat Cells Data Development Disease Energy Metabolism Energy consumption FRAP1 gene Fatty acid glycerol esters Generations Genomics Goals Growth Growth Factor Health Homeostasis Human Knock-out Laboratories Lead Medical center Metabolic Metabolic Control Metabolism Mitochondria Modeling Mus Obesity Outcome PIK3CG gene 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 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

项目摘要

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稳态和产生信号分子。然而，绝大多数人没有棕色脂肪。这严重偏向于使用老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，并建立更好的人性化模型用于临床前研究。以下是我们对生长因子/PI3K/mTOR 作用的机制探索为了了解棕色脂肪的形成和代谢，我们意外地生成了一个小鼠模型没有明显的经典棕色脂肪，我们称之为无 BAT 小鼠。不含 BAT 的小鼠在正常情况下出生孟德尔比率，完全存活，具有正常繁殖能力，且效果100%渗透。基于我们令人兴奋的初步数据，该应用的中心假设是完全缺乏 UCP1 与 UCP1 敲除小鼠相比，BAT-less 小鼠中的表达细胞会导致明显的肥胖效应。测试根据这一假设，我们开发了一套独特的体内模型工具包，包括新的报告小鼠模型以及使用整只小鼠和组织透明谱系追踪技术、基因组学的多学科方法和最先进的代谢表型技术。在目标 1 中，我们将批判性地、明确地确定是否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-less 中丢失 UCP1 表达细胞。在目标2中，我们将使用不含BAT的小鼠来测试BAT能量的贡献消耗对全身代谢和肥胖倾向的影响与 UCP1 无关。不含 BAT 的小鼠是预计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，不含 BAT 的小鼠将向更人性化、更广泛有用的小鼠模型迈出一步。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia.

单细胞转录组学鉴定脂肪组织 CD271 祖细胞可增强肢体缺血的血管生成。

DOI：
发表时间：
2023-02-13
期刊：
影响因子：
0
作者：
Inoue, Oto;Goten, Chiaki;Hashimuko, Daiki;Yamaguchi, Kosei;Takeda, Yusuke;Nomura, Ayano;Ootsuji, Hiroshi;Takashima, Shinichiro;Iino, Kenji;Takemura, Hirofumi;Halurkar, Manasi;Lim, Hee;Hwa, Vivian;Sanchez;Usui, Soichiro
通讯作者：
Usui, Soichiro

Single-cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia.

单细胞转录组学鉴定脂肪组织 CD271 祖细胞可增强肢体缺血的血管生成。

DOI：
发表时间：
2023-12-19
期刊：
影响因子：
0
作者：
Inoue, Oto;Goten, Chiaki;Hashimuko, Daiki;Yamaguchi, Kosei;Takeda, Yusuke;Nomura, Ayano;Ootsuji, Hiroshi;Takashima, Shinichiro;Iino, Kenji;Takemura, Hirofumi;Halurkar, Manasi;Lim, Hee;Hwa, Vivian;Sanchez;Usui, Soichiro
通讯作者：
Usui, Soichiro