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:10313122
- 负责人:
- 金额:$ 4.12万
- 依托单位:
- 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:
- 关键词:ACTA1 geneAffectAmericanAnabolismAnimal ModelAreaAryl Hydrocarbon ReceptorAtrophicAutomobile DrivingAutophagocytosisBinding ProteinsBioenergeticsBiologyCachexiaCalpainCaspaseCatabolismChronicChronic Kidney FailureCytochrome P450DataDependovirusDevelopmentDialysis procedureEnzymesFatigueFellowshipFoundationsFunctional disorderGDF8 geneGeneticGenetic TranscriptionGoalsGrantHand StrengthHemodialysisHumanImpairmentIndicanIngestionInternationalKidneyKidney TransplantationKnock-outKynurenic AcidKynurenineLigandsLinkLiteratureManuscriptsMechanicsMentorsMetabolismMitochondriaModernizationMolecularMolecular BiologyMusMuscleMuscle CellsMuscle FibersMuscle MitochondriaMuscle ProteinsMuscular AtrophyMyopathyPathologyPathway interactionsPatientsPhenocopyPhysiologyPlayProductionPropertyProtein BiosynthesisProteinsProteomicsPublishingQuality of lifeReactive Oxygen SpeciesReceptor ActivationRenal functionResearchRespiratory physiologyRodent ModelRoleScientistSkeletal MuscleSymptomsSystemTamoxifenTestingToxic effectToxinTrainingTraining ProgramsTransgenic OrganismsTryptophanUbiquitinUremiaWorkWritingXenobiotic MetabolismXenobioticsaryl hydrocarbon receptor ligandbasecareerexperimental studyin vivoindoleacetic acidknock-downmitochondrial dysfunctionmulticatalytic endopeptidase complexnovelpre-doctoralpreventpromoterprotective effectprotein degradationprotein metabolitereceptorreceptor bindingrecombinase-mediated cassette exchangesenior facultyskeletalskill acquisitionskillssmall hairpin RNAsolutesymposiumwasting
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
慢性肾脏病 (CKD) 伴有进行性衰弱性肌病,其特征为
肌肉萎缩、虚弱和疲劳。激活蛋白水解途径,包括泛素蛋白酶体
系统、半胱天冬酶/钙蛋白酶、肌肉生长抑制素和自噬失调被认为是致病因素
用于肌肉萎缩和患者生活质量下降。尽管有大量文献,但系统性分子
将肾功能受损与肌肉中这些通路的激活联系起来的机制仍然未知。一个
肾脏的主要功能是清除体内摄入或内源产生的废物
通过正常的新陈代谢。然而,CKD 会导致代谢物的滞留和积累,称为尿毒症。
其中许多代谢物源自色氨酸通过吲哚和犬尿氨酸途径的分解代谢
包括;硫酸吲哚酚、L-犬尿氨酸、犬尿酸和吲哚-3-乙酸,它们是芳基的配体
碳氢化合物受体(AHR),外源代谢的转录调节因子。 AHR 通常上调
解毒途径,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患有 CKD 的小鼠和人类骨骼肌中 AHR 的强烈激活。
此外,用色氨酸衍生的 AHR 配体处理肌肉细胞会导致线粒体功能障碍,
这是通过用短发夹 RNA 对 AHR 进行基因敲除来预防的。最后,表达一个
肌肉细胞中的组成型活性 AHR 受体模仿尿毒症代谢物暴露,导致萎缩和
线粒体功能障碍。根据这些初步数据,我建议检验我的假设:慢性
AHR 的激活在 CKD 相关肌病中起着因果作用。目标 1 将确定是否针对肌肉
敲除 AHR 可防止 CKD 小鼠出现肌肉萎缩和线粒体功能障碍
Cre-lox 系统和他莫昔芬的递送可在 CKD 发作时诱导 AHR 的肌肉特异性敲除。
目标 2 将测试通过 AAV 递送的组成型 AHR 激活是否足以导致肌肉萎缩和
肾功能正常的小鼠线粒体功能障碍。详细的培训计划,其中包括
初级/高级教师,涉及分子生物学、肌肉力学、
线粒体能量学和肾脏生理学已得到发展。该申请将收到额外的
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。完成目标和培训计划
在线粒体功能分析、肌肉生物学和收缩功能、肾脏
生理学、蛋白质合成和降解以及蛋白质组学,这将为我的学习奠定坚实的基础。
职业目标。
项目成果
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{{ truncateString('Trace Thome', 18)}}的其他基金
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
- 批准号:
10455468 - 财政年份:2021
- 资助金额:
$ 4.12万 - 项目类别:
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
- 批准号:
10670948 - 财政年份:2021
- 资助金额:
$ 4.12万 - 项目类别:
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