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

Site-1 蛋白酶在骨骼肌代谢和运动耐力调节中的作用

• 批准号: 10630296
• 负责人: Rita Thomas Brookheart
• 金额: $ 6.74万
• 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 2024-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630296
• 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; 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; 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.

项目总结 肥胖与心脏代谢异常的发生率相关，并增加患心脏病的风险 心血管疾病(CVD)和2型糖尿病。改善这些心脏代谢性疾病的严重程度 读数与改善疾病结局和降低心血管疾病风险有关。常见的方法来 治疗肥胖症包括饮食和锻炼等生活方式干预。锻炼也是一种关键的治疗选择 用于心力衰竭患者和处理与2型糖尿病相关的心血管疾病风险因素。虽然锻炼 改善患者的预后，长期坚持锻炼对许多患者来说是困难的， 不管健康状况如何。心力衰竭和肥胖等疾病与骨骼紊乱有关 肌肉功能和新陈代谢(其机制尚不完全清楚)和患者可能 锻炼时遇到困难。定期锻炼的好处强调了干预措施的必要性 提倡运动耐量。我们已经鉴定了高尔基体驻留蛋白，S1P，作为一个新的 骨骼肌代谢调节剂和运动耐力。后续激活需要S1P 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 压力调节器ATF6。虽然已知S1P在调节多种途径中发挥重要作用，但这些途径涉及 到目前为止，S1P在骨骼肌代谢中的作用：脂代谢、自噬和内质网应激信号 仍然不为人知。我们建议的研究将达到以下目的：(1)阐明S1P在 我们的骨骼肌特异性S1P基因敲除的骨骼肌在健康条件下的代谢和功能 和(2)确定S1P在肥胖相关的骨骼肌功能障碍和心脏代谢中的功能 使用饮食诱导的肥胖小鼠模型。这位候选人已经有很强的 S1P生物学和细胞应激途径，这个K01奖将为她提供必要的培训和 在中间代谢、骨骼肌功能和运动生理学方面的专业知识 完成拟议的研究。她提出的职业发展计划包括：(A)每季度与 她的指导委员会(由代谢、心血管和运动研究方面的专家组成) 在指导初级教员成为成功的独立调查员方面有良好的记录，(B) 相关课程和研讨会/会议，以及(C)一对一的个人辅导会议。这些 各项活动对于顺利完成拟议研究和实现 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S1P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，以开发代谢性疾病的治疗干预措施。