权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10421052
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
项目类别：
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/10421052
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

项目摘要

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