Excellence in Research - Investigating Smooth Muscle-based Regulation of Non-shivering Thermogenesis

卓越的研究 - 研究基于平滑肌的非颤抖产热调节

• 批准号: 2100832
• 负责人: Sharon Francis
• 金额: $ 87.38万
• 依托单位: Morehouse School of Medicine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2100832&HistoricalAwards=false
• 关键词: Excellence; Research; Investigating; Smooth; Muscle

This project tests the hypothesis that smooth muscle contributes significantly to heat production during cold acclimation in mice, and investigates the mechanisms of heat production in these cells. Mammals and birds adjust to a cold environment by stimulating biochemical processes in specific cells to increase heat production within the body, allowing survival at cold temperatures. To date, the specific cells known to produce heat for body temperature regulation are those that comprise brown fat and skeletal muscle. This research will examine a previously unrecognized potential for smooth muscle cells to produce heat to keep animals warm when housed at a cold temperature. The study will use a unique animal model in which a protein that stimulates biochemical processes that enhance heat production is removed from smooth muscle cells. The knowledge gained from these studies may have important implications for proper cell function and body weight maintenance. Rigorous academic and civic training opportunities will be provided to under-represented minority graduate students pursuing careers in the STEM workforce. A new course that incorporates didactic and hands-on training will be developed to expand the knowledge of under-represented students in temperature regulation. Additionally, this project will engage K-12 public school students and the lay community to demystify the scientific research process and expose the lay minority community to science. This project will establish a novel paradigm for thermoregulation and energy expenditure in mammals and broaden the participation of under-represented graduate students in STEM-related basic research. The project tests the hypothesis that smooth muscle regulates energy expenditure and contributes to temperature homeostasis through a serum and glucocorticoid-inducible kinase 1 (SGK1)-based mechanism of non-shivering thermogenesis (NST). NST is the production of internal body heat and is crucial for maintenance of core body temperature and energy expenditure. Experiments will examine the contribution and function of smooth muscle and SGK1 in thermoregulation and energy expenditure in smooth-muscle-cell (SMC)-specific SGK1 null mice under thermoneutral housing temperatures and cold-challenged conditions. Preliminary studies demonstrate that thermogenic processes mediated by the mitochondria are enhanced in SMC-specific SGK1 null mice. This project will establish a novel paradigm for NST by uncovering a previously unknown thermogenic role for SGK1 in smooth muscle. The research will help to broaden scientific knowledge of how endothermic animals are able to maintain body temperature and ensure survival, and could lead to future applications for reducing obesity in humans. In addition, this proposal will facilitate training opportunities for under-represented minority students who are enrolled in the graduate programs at Morehouse School of Medicine. This award will provide an opportunity for students to conduct research, contribute to the body of scientific literature, and receive scientific, academic and civic mentorship to support future employment in STEM-related careers and contribute to the diversification of the American scientific workforce. Community-based projects involving lay minority members will be incorporated to enhance their exposure to the scientific process.This award is co-funded by the Historically Black Colleges and Universities - Excellence in Research Program in the Office of Integrative Activities and the Physiological Mechanisms and Biomechanics Program in the Division of Integrative Organismal Systems, Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目验证了在小鼠冷适应过程中，平滑肌对产热有显著贡献的假说，并研究了这些细胞产热的机制。哺乳动物和鸟类通过刺激特定细胞中的生化过程来适应寒冷的环境，以增加体内的热量产生，从而在寒冷的温度下生存。到目前为止，已知的为体温调节产生热量的特定细胞是那些由棕色脂肪和骨骼肌组成的细胞。这项研究将检验一种以前未被认识到的潜力，即当动物被安置在寒冷的温度下时，平滑肌细胞产生热量来保暖。这项研究将使用一种独特的动物模型，在这种模型中，一种刺激生化过程的蛋白质会从平滑肌细胞中移除，从而提高产热能力。从这些研究中获得的知识可能对适当的细胞功能和体重维持有重要意义。将向在STEM劳动力中寻求职业生涯的人数不足的少数族裔研究生提供严格的学术和公民培训机会。将开发一门结合授课和动手培训的新课程，以扩大未被充分代表的学生在温度调节方面的知识。此外，该项目将邀请K-12公立学校的学生和非专业人士社区揭开科学研究过程的神秘面纱，并使非专业少数群体社区接触到科学。该项目将为哺乳动物的体温调节和能量消耗建立一个新的范例，并扩大未被充分代表的研究生对STEM相关基础研究的参与。该项目通过一种基于血清和糖皮质激素诱导的蛋白1(SGK1)的非颤抖产热(NST)机制来检验这一假说，即平滑肌通过调节能量消耗和促进温度动态平衡。NST是体内热量的产生，对维持核心体温和能量消耗至关重要。实验将在温中温箱温度和冷挑战条件下，在SMC特异性SGK1缺失小鼠中检测SMC和SGK1在体温调节和能量消耗中的贡献和功能。初步研究表明，在SMC特异性SGK1缺失小鼠中，线粒体介导的生热过程得到增强。该项目将通过揭示先前未知的SGK1在平滑肌中的生热作用，为NST建立一个新的范例。这项研究将有助于拓宽吸热动物如何维持体温并确保生存的科学知识，并可能导致未来应用于减少人类肥胖。此外，这项提案将为莫尔豪斯医学院研究生课程中代表人数不足的少数族裔学生提供培训机会。该奖项将为学生提供进行研究的机会，为科学文献的主体做出贡献，并接受科学、学术和公民指导，以支持未来在STEM相关职业中的就业，并为美国科学劳动力的多样化做出贡献。涉及非专业少数群体成员的社区项目将被纳入，以增加他们对科学过程的接触。该奖项由历史上的黑人学院和大学-综合活动办公室的卓越研究计划和生物科学理事会综合组织系统部门的生理机制和生物力学计划共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。