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

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 慢性肾脏病(CKD)伴有进行性衰弱的肌病,其特征是 肌肉萎缩、虚弱和疲劳。包括泛素蛋白酶体在内的蛋白分解途径的激活 系统、半胱氨酸天冬氨酸酶/钙蛋白酶、肌肉抑制素和自噬失调被认为是致病因素。 治疗肌肉萎缩和降低患者的生活质量。尽管有这么多文献,系统的分子 将肾功能受损与肌肉中这些通路的激活联系起来的机制(S)仍不清楚。一个 肾脏的主要功能是清除体内摄取或产生的废物。 通过正常的新陈代谢。然而,CKD会导致代谢物的滞留和积聚,称为尿毒症。 许多这样的代谢物是通过吲哚和犬尿氨酸途径从色氨酸分解代谢中获得的。 包括芳基的配体吲哚基硫酸酯、L-犬尿氨酸、犬尿酸和吲哚-3-乙酸 碳氢化合物受体(AHR),外源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,患有慢性肾脏病的小鼠和人类的骨骼肌中AHR都有很强的激活。 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, 这是通过用短发夹状RNA基因敲除AHR来防止的。最后,A的表达式 肌细胞中具有结构性活性的AHR受体模拟尿毒症代谢物暴露导致萎缩和 线粒体功能障碍。基于这些初步数据,我建议检验我的假设 AHR的激活在CKD相关性肌病中起着因果作用。目标1将确定肌肉特异性 AHR基因敲除对慢性肾脏病小鼠肌肉萎缩和线粒体功能障碍的保护作用 Cre-lox系统和他莫昔芬的传递诱导CKD发病时肌肉特异性的AHR基因敲除。 目标2将测试通过AAV传递的结构性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。一项详细的培训计划,其中包括 初级/高级教员,涉及分子生物学、肌肉力学、 线粒体能量学和肾脏生理学已经发展起来。应用程序将收到额外的 职业指导,包括助学金/手稿写作、演示技能和职业发展,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、肾脏等方面进行出色的培训 生理学、蛋白质合成和降解,以及蛋白质组学,这将为我的 职业目标。

项目成果

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Trace Thome其他文献

Trace Thome的其他文献

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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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