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Chronic aryl hydrocarbon receptor activation and skeletal myopathy in chronic kidney disease

慢性肾病中的慢性芳烃受体激活和骨骼肌病

基本信息

批准号：
10455468
负责人：
Trace Thome
金额：
$ 4.31万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2024-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455468
关键词：
ACTA1 gene Affect American Anabolism Animal Model Area Aryl Hydrocarbon Receptor Atrophic Automobile Driving Autophagocytosis Binding Proteins Bioenergetics Biology Cachexia Calpain Caspase Catabolism Chronic Chronic Kidney Failure Cre lox recombination system Cytochrome P450 Data Dependovirus Development Dialysis procedure Enzymes Fatigue Fellowship Foundations Functional disorder GDF8 gene Genetic Genetic Transcription Goals Grant Hand Strength Hemodialysis Human Impairment Indican Ingestion International Kidney Kidney Transplantation Knock-out Kynurenic Acid Kynurenine Ligands Link Literature Manuscripts Mechanics Mentors Metabolism Mitochondria Modernization Molecular Molecular Biology Mus Muscle Muscle Cells Muscle Fibers Muscle Mitochondria Muscle Proteins Muscular Atrophy Myopathy Pathology Pathway interactions Patients Phenocopy Physiology Play Production Property Protein Biosynthesis Proteins Proteomics Publishing Quality of life Reactive Oxygen Species Receptor Activation Renal function Research Respiratory physiology Rodent Model Role Scientist Skeletal Muscle Symptoms System Tamoxifen Testing Toxic effect Toxin Training Training Programs Transgenic Organisms Tryptophan Ubiquitin Uremia Work Writing Xenobiotic Metabolism Xenobiotics aryl hydrocarbon receptor ligand base career experimental study in vivo indoleacetic acid knock-down mitochondrial dysfunction multicatalytic endopeptidase complex novel pre-doctoral prevent promoter protective effect protein degradation protein metabolite receptor receptor binding senior faculty skeletal skill acquisition skills small hairpin RNA solute symposium wasting

项目摘要

Abstract Chronic Kidney Disease (CKD) is accompanied by a progressively debilitating myopathy characterized by muscle wasting, weakness, and fatigue. Activation of proteolytic pathways including the ubiquitin proteasome system, caspases/calpains, myostatin, and dysregulation of autophagy have been implicated as causal factors for muscle wasting and reduced quality of life in patients. Despite this body of literature, the systemic molecular mechanism(s) linking impaired kidney function to activation of these pathways in muscle remains unknown. A major function of the kidneys is to rid the body of waste materials that are ingested or produced endogenously by normal metabolism. However, CKD results in the retention and accumulation of metabolites, termed uremia. A number of these metabolites are derived from tryptophan catabolism through indolic and kynurenine pathways including; indoxyl sulfate, L-kynurenine, kynurenic acid, and indole-3-acetic acid which are ligands for the aryl hydrocarbon receptor (AHR), a transcriptional regulator of xenobiotic metabolism. The AHR usually upregulates detoxifying pathways such as cytochrome P450 enzymes, however chronic activation of the AHR can be toxic. My preliminary data reveals robust AHR activation in skeletal muscle of both mice and humans with CKD. Furthermore, treatment of muscle cells with tryptophan-derived AHR ligands results in mitochondrial dysfunction, which was prevented by genetic knockdown of the AHR with short hairpin RNA. Lastly, expression of a constitutively active AHR receptor in muscle cells mimicked uremic metabolite exposure causing atrophy and mitochondrial dysfunction. Based on these preliminary data, I propose to test my hypothesis that chronic activation of the AHR plays a causal role in CKD-associated myopathy. Aim 1 will determine if muscle-specific knockout of the AHR protects against muscle atrophy and mitochondrial dysfunction in mice with CKD using a Cre-lox system and delivery of tamoxifen to induce muscle specific knockout of the AHR at the onset of CKD. Aim 2 will test whether constitutive AHR activation via AAV delivery is sufficient to cause muscle atrophy and mitochondrial dysfunction in mice with normal kidney function. A detailed training program with a mixture of junior/senior faculty that involves specific research skill enhancement in molecular biology, muscle mechanics, mitochondrial energetics, and renal physiology has been developed. The application will receive additional career mentoring involving grant/manuscript writing, presentation skills, and professional development including participation in national and international scientific conferences. Completion of the aims and training plan will result in excellent training in mitochondrial functional analysis, muscle biology and contractile function, renal physiology, protein synthesis and degradation, and proteomics which will provide a strong foundation for my career goals.

摘要慢性肾病（CKD）伴随进行性衰弱性肌病，其特征在于肌肉萎缩无力和疲劳包括泛素蛋白酶体在内的蛋白水解途径的激活系统、半胱天冬酶/钙蛋白酶、肌生长抑制素和自噬失调被认为是致病因素导致肌肉萎缩和患者生活质量下降。尽管有这样的文献，系统的分子将受损的肾功能与肌肉中这些途径的激活联系起来的机制仍然未知。一肾的主要功能是清除体内摄入或内源性产生的废物通过正常的新陈代谢。然而，CKD导致代谢物的保留和积累，称为尿毒症。这些代谢物中的许多是通过吲哚和犬尿氨酸途径从色氨酸催化剂衍生而来的包括：硫酸吲哚酚、L-犬尿氨酸、犬尿烯酸和吲哚-3-乙酸，它们是芳基的配体，碳氢化合物受体（AHR），异生物质代谢的转录调节因子。AHR通常会上调解毒途径，如细胞色素P450酶，然而，AHR的慢性激活可能是有毒的。我的初步数据显示，在患有CKD的小鼠和人类的骨骼肌中，AHR都有强烈的激活。此外，用来源于Escherichan的AHR配体处理肌细胞导致线粒体功能障碍，这是通过用短发夹RNA基因敲低AHR来防止的。最后，A的表达式肌细胞中的组成型活性AHR受体模拟尿毒症代谢物暴露引起萎缩，线粒体功能障碍基于这些初步的数据，我建议检验我的假设， AHR的激活在CKD相关肌病中起因果作用。目标1将确定肌肉特异性 AHR基因敲除可保护CKD小鼠免受肌肉萎缩和线粒体功能障碍， Cre-lox系统和他莫昔芬的递送在CKD发作时诱导AHR的肌肉特异性敲除。目的2将测试通过AAV递送的组成型AHR激活是否足以引起肌肉萎缩，肾功能正常小鼠的线粒体功能障碍。详细的培训计划，初级/高级教师，涉及分子生物学，肌肉力学，线粒体能量学和肾生理学的研究。申请人将获得额外的职业指导，涉及资助/手稿写作、演讲技巧和专业发展，包括参加国家和国际科学会议。目标和培训计划的完成将结果在线粒体功能分析，肌肉生物学和收缩功能，肾功能，生理学，蛋白质合成和降解，以及蛋白质组学，这将为我提供坚实的基础职业目标。