Site-1 Protease in the regulation of skeletal muscle metabolism and exercise endurance

项目摘要 肥胖与心血管代谢异常的发生率有关， 心血管疾病（CVD）和2型糖尿病。这些心脏代谢疾病严重程度的改善 读数与改善疾病结果和降低CVD风险相关。的共同办法 治疗肥胖包括生活方式干预，如饮食和锻炼。运动也是一个关键的治疗选择 用于心力衰竭患者和应对与2型糖尿病相关的心血管疾病风险因素。虽然运动 改善患者的治疗效果，长期坚持锻炼对许多患者来说是困难的， 无论健康状况如何。像心力衰竭和肥胖症这样的疾病， 肌肉功能和代谢（其机制尚未完全了解），患者可能 练习困难。定期锻炼的好处强调了干预措施的必要性， 提高运动耐力。我们已经确定高尔基体驻留蛋白，位点1蛋白酶（S1 P），作为一种新的 骨骼肌代谢和运动耐力的调节剂。后续激活需要S1 P 几个关键的转录因子，包括固醇调节元件结合蛋白家族和ER 应激调节因子ATF 6。虽然已知S1 P在调节参与的多种途径中发挥重要作用， 脂质代谢、自噬和内质网应激信号，迄今为止，S1 P在骨骼肌代谢中的作用 仍然未知。本研究的主要目的是：（1）阐明S1 P在细胞内的功能， 在我们的骨骼肌特异性S1 P基因敲除中，健康条件下骨骼肌代谢和功能 （2）确定S1 P在肥胖相关的骨骼肌功能障碍和心脏代谢障碍中的作用。 使用饮食诱导的肥胖症小鼠模型观察异常。这位候选人已经有了很强的背景， S1 P生物学和细胞应激途径，这个K 01奖将为她提供必要的培训， 在中间代谢，骨骼肌功能和运动生理学的专业知识，成功地 完成拟议的研究。她提议的职业发展计划包括：（a）与下列人员举行季度会议： 她的导师委员会（由代谢、心血管和运动研究专家组成）， 在指导初级教师成为成功的独立调查人员方面有良好的记录，（B） 相关课程和研讨会/会议，以及（c）一对一的个别导师会议。这些 活动对于成功完成拟议的研究和实现 候选人的长期目标是领导一个成功的独立实验室，将她在 细胞应激途径和S1 P生物学与建议的指导目标，以发现新的机制， 肥胖相关的心血管疾病和骨骼肌功能障碍。她的实验室未来的工作也将 专注于她发现的靶向机制，以开发代谢疾病的治疗干预措施。

PROJECT SUMMARY Obesity is associated with an incidence of cardiometabolic abnormalities and an increased risk for cardiovascular disease (CVD) and type 2 diabetes. Improvements in the severity of these cardiometabolic readouts are associated with improved disease outcomes and reduced risk for CVD. Common approaches to treat obesity include lifestyle interventions such as diet and exercise. Exercise is also a key treatment option for heart failure patients and for tackling CVD risk factors associated with type 2 diabetes. Although exercise improves patient outcomes, long-term adherence to an exercise routine is difficult for many patients, regardless of health status. Diseases like heart failure and obesity are associated with disrupted skeletal muscle function and metabolism (the mechanisms of which are not yet fully understood) and patients may experience difficulty exercising. The benefits of regular exercise underscore the need for interventions that promote exercise tolerance. We have identified the Golgi-resident protein, Site-1 Protease (S1P), as a novel regulator of skeletal muscle metabolism and exercise endurance. S1P is required for the subsequent activation of several key transcription factors, including the sterol regulatory element-binding protein family and the ER stress regulator ATF6. While S1P is known to play important roles in regulating diverse pathways involved in lipid metabolism, autophagy, and ER stress signaling, to date, the role of S1P in skeletal muscle metabolism remains unknown. Our proposed studies will undertake the following Aims: (1) elucidate the function of S1P in skeletal muscle metabolism and function under healthy conditions in our skeletal muscle-specific S1P knockout mice and (2) define a function for S1P in obesity-associated skeletal muscle dysfunction and cardiometabolic abnormalities using a diet-induced obesity mouse model. The candidate already has a strong background in S1P biology and cellular stress pathways, this K01 award will provide her with the necessary training and expertise in intermediary metabolism, skeletal muscle function, and exercise physiology to successfully complete the proposed studies. Her proposed career development plan includes: (a) quarterly meetings with her Mentorship Committee (composed of experts in metabolic, cardiovascular, and exercise research) who have an excellent track record of mentoring junior faculty into successful independent investigators, (b) relevant coursework and seminars/conferences, and (c) one-on-one individual mentor meetings. These activities are crucial for the successful completion of the proposed studies and for achievement of the candidate's long-term goal of leading a successful independent lab that integrates her strong background in cellular stress pathways and S1P biology with the proposed Mentoring Goals to discover novel mechanisms in obesity-associated cardiovascular disease and skeletal muscle dysfunction. Future work in her lab will also focus on targeting mechanisms she uncovers to develop therapeutic interventions for metabolic disease.