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：
10670948
负责人：
Trace Thome
金额：
$ 3.79万
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 2024-05-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670948
关键词：
ACTA1 gene Ablation Acetic Acids 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 Drug Metabolic Detoxication 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 Membrane 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 Phenotype 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 aryl hydrocarbon receptor ligand 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.

抽象的慢性肾脏疾病（CKD）伴随着一种逐渐使人衰弱的肌病肌肉浪费，无力和疲劳。包括泛素蛋白酶体的蛋白水解途径的激活系统，胱天蛋白酶/钙蛋白酶，肌生抑素和自噬的失调已被视为因果因素肌肉浪费和患者生活质量降低。尽管文献有很多文献，但全身分子将受损的肾功能与这些肌肉中这些途径激活联系起来的机制仍然未知。一个肾脏的主要功能是消除被摄入或内源产生的废物的物体通过正常代谢。但是，CKD导致代谢物的保留和积累，称为尿毒症。这些代谢产物中的许多是通过色氨酸分解代谢来源的，包括;吲哚基硫酸盐，l-京难是，雌二酸和吲哚-3-乙酸，它们是芳基的配体碳氢化合物受体（AHR），一种异种生物代谢的转录调节剂。 AHR通常上调排毒途径，例如细胞色素P450酶，但是AHR的慢性激活可能是有毒的。我的初步数据揭示了使用CKD的小鼠和人类的骨骼肌中强大的AHR激活。此外，用色氨酸衍生的AHR配体治疗肌肉细胞会导致线粒体功能障碍，用短发夹RNA遗传AHR的遗传敲低阻止了这种情况。最后，表达肌肉细胞中的组成性活性AHR受体模仿尿毒症代谢产物，导致萎缩和线粒体功能障碍。基于这些初步数据，我建议测试我的假设 AHR的激活在与CKD相关的肌病中起因果作用。 AIM 1将确定肌肉特异性是否 AHR的敲除可以使用A的CKD中的小鼠中的肌肉萎缩和线粒体功能障碍 Cre-lox系统和他莫昔芬在CKD发作时诱导AHR的肌肉特异性敲除。 AIM 2将测试通过AAV传递的组成型AHR激活是否足以引起肌肉萎缩和肾功能正常的小鼠的线粒体功能障碍。详细的培训计划，混合涉及分子生物学，肌肉力学的特定研究技能的初级/高级教师，线粒体能量学和肾脏生理学已经开发。该申请将获得额外职业指导涉及赠款/手稿写作，演示技巧和专业发展，包括参加国家和国际科学会议。目标和培训计划的完成将在线粒体功能分析，肌肉生物学和收缩功能，肾脏方面进行了出色的培训生理，蛋白质合成和降解以及蛋白质组学，这将为我的我职业目标。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reversible Thiol Oxidation Increases Mitochondrial Electron Transport Complex Enzyme Activity but Not Respiration in Cardiomyocytes from Patients with End-Stage Heart Failure.

DOI：
10.3390/cells11152292
发表时间：
2022-07-25
期刊：
Cells
影响因子：
6
作者：
通讯作者：

NMR Spectroscopy Identifies Chemicals in Cigarette Smoke Condensate That Impair Skeletal Muscle Mitochondrial Function.

DOI：
10.3390/toxics10030140
发表时间：
2022-03-14
期刊：
Toxics
影响因子：
4.6
作者：
Khattri RB;Thome T;Fitzgerald LF;Wohlgemuth SE;Hepple RT;Ryan TE
通讯作者：
Ryan TE

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.

DOI：
10.1161/circresaha.123.323161
发表时间：
2023-10-27
期刊：
CIRCULATION RESEARCH
影响因子：
20.1
作者：
Pass, Caroline G.;Palzkill, Victoria;Tan, Jianna;Kim, Kyoungrae;Thome, Trace;Yang, Qingping;Fazzone, Brian;Robinson, Scott T.;O'Malley, Kerri A.;Yue, Feng;Scali, Salvatore T.;Berceli, Scott A.;Ryan, Terence E.
通讯作者：
Ryan, Terence E.

Mitochondrial Bioenergetic and Proteomic Phenotyping Reveals Organ-Specific Consequences of Chronic Kidney Disease in Mice.

DOI：
10.3390/cells10123282
发表时间：
2021-11-24
期刊：
Cells
影响因子：
6
作者：
Thome T;Coleman MD;Ryan TE
通讯作者：
Ryan TE

IGF-1 Therapy Improves Muscle Size and Function in Experimental Peripheral Arterial Disease.

DOI：
10.1016/j.jacbts.2022.12.006
发表时间：
2023-06
期刊：
JACC-BASIC TO TRANSLATIONAL SCIENCE
影响因子：
9.7
作者：
Dong, Gengfu;Moparthy, Chatick;Thome, Trace;Kim, Kyoungrae;Yue, Feng;Ryan, Terence E.
通讯作者：
Ryan, Terence E.