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

位点 1 蛋白酶在骨骼肌代谢和运动耐力调节中的作用

• 批准号: 10186796
• 负责人: Rita Thomas Brookheart
• 金额: $ 12.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186796
• 关键词: ATF6 gene; Achievement; Actins; Adherence; Autophagocytosis; Binding Proteins; Biogenesis; Biology; Blood; Body Composition; Cardiac Myocytes; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cellular Stress; Coupled; Data; Development Plans; Disease; Disease Outcome; Dyslipidemias; Enterobacteria phage P1 Cre recombinase; Enzymes; Exercise; Exercise Physiology; Exercise Test; Exercise Tolerance; Exhibits; Faculty; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Glycogen; Goals; Golgi Apparatus; Health; Health Benefit; Health Status; Heart failure; Human; Hypertension; Impairment; Incidence; Individual; Insulin Resistance; Intervention; Knockout Mice; Liver; Longevity; LoxP-flanked allele; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Muscle; Muscle function; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated cardiovascular disease; Organ; Oxygen Consumption; Pathway interactions; Patient-Focused Outcomes; Patients; Physical activity; Physiological; Play; Predisposition; Protease Inhibitor; Protein Family; Proteins; Regulation; Regulatory Element; Reporting; Research; Research Personnel; Risk Factors; Role; Severities; Signal Transduction; Skeletal Muscle; Sterols; Therapeutic Intervention; Time; Training; Triglycerides; Type 2 diabetic; Ventricular; Ventricular Function; Viral; Wild Type Mouse; Work; cardiometabolism; cardiovascular disorder risk; career development; diabetic patient; diet and exercise; diet-induced obesity; dietary control; endoplasmic reticulum stress; endurance exercise; enzyme substrate; exercise intolerance; exercise regimen; exercise training; exhaustion; experience; fatty acid metabolism; fatty acid oxidation; glucose tolerance; improved; improved outcome; innovation; insulin sensitivity; lifestyle intervention; lipid metabolism; meetings; metabolomics; mouse model; muscle metabolism; novel; obesogenic; oxidation; promoter; protease SM; respiratory; sedentary; site-1 protease; skeletal; skeletal muscle metabolism; symposium; transcription factor; transcriptome sequencing

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.

项目摘要 肥胖与心脏代谢异常的发生率有关，并增加 心血管疾病（CVD）和2型糖尿病。这些心脏代谢的严重程度的改善 读数与改善疾病结局和CVD风险降低有关。常见的方法 治疗肥胖包括生活方式干预，例如饮食和运动。运动也是关键的治疗选择 用于心力衰竭患者以及解决与2型糖尿病有关的CVD危险因素。虽然运动 改善患者的预后，对于许多患者而言，很难长期遵守运动常规， 不论健康状况如何。心力衰竭和肥胖等疾病与骨骼中断有关 肌肉功能和代谢（其机制尚未完全理解），患者可能 经历锻炼困难。定期运动的好处强调了对干预措施的需求 促进运动耐受性。我们已经确定Golgi居民蛋白Site-1蛋白酶（S1P）是一种新颖 骨骼肌代谢和运动耐力的调节剂。随后的激活需要S1P 在几种关键转录因子中，包括固醇调节元素结合蛋白家族和ER 压力调节器ATF6。众所周知，S1P在调节涉及的各种途径中起着重要作用 迄今为止 仍然未知。我们提出的研究将实现以下目的：（1）阐明S1P在 在我们骨骼肌肉特异性的S1P敲除中，在健康条件下的骨骼肌代谢和功能 小鼠和（2）在肥胖相关骨骼肌肉功能障碍和心脏代谢中定义S1P的功能 使用饮食引起的肥胖小鼠模型的异常。候选人已经有很强的背景 S1P生物学和细胞应力途径，该K01奖将为她提供必要的培训和 中介代谢，骨骼肌功能和运动生理学的专业知识 完成拟议的研究。她提出的职业发展计划包括：（a）与 她的指导委员会（由代谢，心血管和运动研究专家组成） 拥有指导初级教师为成功独立研究人员的出色记录，（b） 相关课程和研讨会/会议，以及（c）一对一的个人导师会议。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，该实验室在 细胞应力途径和S1P生物学具有拟议的指导目标，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。她的实验室的未来工作也将 她专注于靶向机制，以开发用于代谢疾病的治疗干预措施。