Endocannabinoid Regulation of Bone Metabolism in Hibernating Marmots

冬眠土拨鼠骨代谢的内源性大麻素调节

• 批准号: 1854108
• 负责人: Seth Donahue
• 金额: $ 11.85万
• 依托单位: University of Massachusetts Amherst
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1854108&HistoricalAwards=false
• 关键词: Endocannabinoid; Regulation; Bone; Metabolism; Hibernating

One of the goals of comparative physiology is to understand how different physiological systems impact each other. Endocannabinoids are signaling molecules derived from fatty acids that appeared early in evolution and play important roles in regulating numerous physiological processes including those that are altered in hibernation such as bone, fat, and energy metabolism. The research aims to understand how endocannabinoid signaling by fat cells affects bone remodeling in obese, but otherwise healthy hibernating marmots. The planned studies will provide research experiences for undergraduate students to prepare them for advanced education and careers in science. The educational outreach component of this award will help students understand how diet and exercise affect fat accumulation and overall health of organisms. It will also elucidate how some animals have evolved physiological systems that prevent disease during states of obesity and physical inactivity. It will develop an interactive exhibit for K-12 students to explore the differences between the metabolism and physical activity of a hibernating animal and themselves. It will develop research kits for middle school students to measure and understand the calorie content of specific foods. It will also develop a presentation on the unique physiological adaptations in hibernators to underserved K-5 students. Hibernating mammals demonstrate remarkable resilience by having evolved physiological mechanisms that allow them to survive extreme physiological and environmental conditions for prolonged periods of time. Physical inactivity, obesity, and anorexia are well known to negatively impact bone metabolism and structure in non-hibernating animals. However, the physical inactivity, obesity, and anorexia that occur during hibernation do not negatively affect bone in marmots. The research will investigate the role of the endocannabinoid system in preventing bone loss in hibernating marmots. The research will test the general hypothesis that the endocannabinoid system regulates bone metabolism during hibernation to prevent bone loss. The project will undertake an interdisciplinary approach to understanding the role of paracrine signaling from bone marrow adipocytes in endocannabinoid regulated bone metabolism during hibernation. Novel targeted mass spectrometry methodology to measure tissue levels of endocannabinoid ligands, with greater sensitivity than previously reported, will be used to measure endocannabinoid levels in marmot serum, bone, and adipose tissue. Pharmacological blocking will be used to assess the role of specific components of the endocannabinoid system in regulating bone remodeling and structure during hibernation. Additionally, the methodology and results from the study will provide the conceptual framework for modeling how the endocannabinoid system regulates metabolism in other physiological systems during the extreme conditions of hibernation.

比较生理学的目标之一是了解不同的生理系统是如何相互影响的。内源性大麻素是由脂肪酸衍生的信号分子，在进化早期出现，在调节许多生理过程中发挥重要作用，包括那些在冬眠中改变的生理过程，如骨骼、脂肪和能量代谢。这项研究旨在了解脂肪细胞发出的内源性大麻素信号是如何影响肥胖而非健康冬眠土拨鼠的骨骼重塑的。计划中的研究将为本科生提供研究经验，为他们接受高等教育和从事科学工作做好准备。该奖项的教育推广部分将帮助学生了解饮食和运动如何影响脂肪积累和生物体的整体健康。它还将阐明一些动物是如何进化出在肥胖和缺乏运动状态下预防疾病的生理系统的。它将为K-12学生开发一个互动展览，以探索冬眠动物和他们自己的新陈代谢和身体活动之间的差异。它将为中学生开发研究工具包，以测量和了解特定食物的卡路里含量。它还将为缺乏服务的K-5学生开发一个关于冬眠动物独特生理适应的报告。冬眠的哺乳动物通过进化出的生理机制显示出非凡的适应力，这些生理机制使它们能够在极端的生理和环境条件下长时间生存。众所周知，缺乏运动、肥胖和厌食症会对非冬眠动物的骨骼代谢和结构产生负面影响。然而，冬眠期间发生的身体活动不足、肥胖和厌食症对土拨鼠的骨骼没有负面影响。该研究将调查内源性大麻素系统在防止冬眠土拨鼠骨质流失中的作用。该研究将验证内源性大麻素系统在冬眠期间调节骨骼代谢以防止骨质流失的一般假设。该项目将采用跨学科的方法来了解骨髓脂肪细胞旁分泌信号在内源性大麻素调节的冬眠期间骨代谢中的作用。新型靶向质谱法测量内源性大麻素配体的组织水平，比以前报道的灵敏度更高，将用于测量土拨鼠血清、骨骼和脂肪组织中的内源性大麻素水平。药物阻断将用于评估内源性大麻素系统的特定成分在调节冬眠期间骨重塑和结构中的作用。此外，该研究的方法和结果将为模拟内源性大麻素系统如何在冬眠的极端条件下调节其他生理系统的代谢提供概念框架。