Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
批准号:
10557832
负责人:
Suresh C. Tyagi
金额:
$33.88万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-09-21 至 2025-01-31
关键词:
AngiographyAtrophicAttenuatedBiological AssayBirthBody WeightCRISPR/Cas technologyCell Differentiation processCell LineCell ProliferationChildChronicCollagenCystathionine beta-SynthaseCysteine DesulfhydraseDataDepositionDeteriorationDiameterEndothelial CellsEnzymesExhibitsFOXO1A geneFatigueGDF8 geneGenerationsGenesGenetic TranscriptionGoalsHeterozygoteHomocysteineHomocystinuriaHydrogen SulfideHyperhomocysteinemiaHypoxiaImageImmunohistochemistryImpairmentIn VitroIschemiaIsolated limb perfusionLasersLigationMeasuresMediatingMetabolicModalityMusMuscleMuscle FibersMuscular AtrophyMutationMyopathyNatural regenerationPhosphorylationPlasmaPredispositionProliferatingProto-Oncogene Proteins c-aktRoentgen RaysRoleSignal TransductionSignaling MoleculeSkeletal MuscleStarvationTeenagersTestingTherapeuticTissuesTranscriptTransduction GeneTransgenic MiceTransgenic OrganismsVascular Endothelial Growth Factorsattenuationdensitydesignfemoral arteryfrailtyhypoxia inducible factor 1in vivoknock-downlimb ischemiamuscle regenerationnovelpreventresponsesatellite cellskeletal muscle wastingsmall moleculetissue oxygenationvasculogenesis
中文摘要
由于纯合型胱硫醚β合酶缺乏症(CBS-/-)而患有严重同型胱氨酸尿症的儿童
表现出体重不足、骨骼肌肌病并在青少年时期死亡。尽管携带纯合子CBS的小鼠
突变在出生后不久死亡,杂合子CBS-/+存活。我们的初步数据显示,
酶,CBS和胱硫醚γ-裂解酶(CSE),通过
转化为硫化氢(H2S),在骨骼肌中减少。虽然降低Hcy水平,
H2S的产生是有益的,HHcy导致骨骼肌消耗和脆弱的机制是
未知本项目的长期目标是了解高同型半胱氨酸引起肌肉萎缩的机制,
评估H2S信号在逆转骨骼肌萎缩和肌病中的潜在有益作用。
该建议的中心假设是,HHcy通过以下方式引起骨骼肌退化:
通过促进肌肉萎缩和限制骨骼肌,
再生和H2S逆转了这些变化。我们将通过以下三个具体目标来检验这一假设:
具体目标#1:确定HHcy是否抑制肌肉特异性AKT、HIF-1和AMPK
信号传导并损害血管发生,H2S逆转受损的血管发生。
具体目标#2:确定HHcy是否减弱PGC-1信号传导并刺激萎缩性细胞因子
H2S表达并引起肌肉萎缩,H2S减轻肌肉萎缩。
具体目标#3:为了确定HHcy是否增强TGF-β 1信号传导和肌肉生长抑制素水平,
从而抑制肌肉再生,H2S改善这些变化。
英文摘要
Children born with severe homocystinuria due to homozygous cystathionine beta synthase deficiency (CBS-/-)
exhibit poor body weights, skeletal muscle myopathy and die in teenage. Although mice with homozygous CBS
mutation die shortly after birth, the heterozygous CBS-/+ survives. Our preliminary data suggests that
enzymes, CBS and cystathionine gamma-lyase (CSE) that irreversibly remove homocysteine (Hcy) by
converting to hydrogen sulfide (H2S), are decreased in skeletal muscle. Although lowering of Hcy levels and
generation of H2S is beneficial, the mechanism by which HHcy causes of skeletal muscle wasting and frailty is
unknown. The long-term goal of this project is to understand the mechanism of muscle wasting in HHcy and
evaluate the potential beneficial effects of H2S signaling in reversing skeletal muscle wasting and myopathy.
The central hypothesis of this proposal is that HHcy causes skeletal muscle deterioration by
compromising vasculogenesis, by enhancing muscle atrophy and by limiting skeletal muscle
regeneration and H2S reverses these changes. We will test this hypothesis by following three specific aims:
Specific Aim #1: To determine whether the HHcy inhibits muscle specific AKT, HIF-1, and AMPK
signaling and impairs vasculogenesis and H2S reverses impaired vasculogenesis.
Specific Aim #2: To determine whether the HHcy attenuates PGC-1 signaling and instigates atrogene
expression and causes muscular atrophy and H2S mitigates muscle atrophy.
Specific Aim #3: To determine whether the HHcy enhances TGF-1 signaling and myostatin levels,
thereby suppresses muscle regeneration and H2S ameliorates these changes.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1139/cjpp-2020-0215
发表时间:
2020-07
期刊:
Canadian journal of physiology and pharmacology
影响因子:
2.1
作者:
[Dragana Stanisic;M. Jovanović;Akash K. George;R. Homme;N. Tyagi;S. Tyagi;Mahavir Singh]
通讯作者:
Dragana Stanisic;M. Jovanović;Akash K. George;R. Homme;N. Tyagi;S. Tyagi;Mahavir Singh
DOI:
10.1007/s11010-022-04487-0
发表时间:
2023-01
期刊:
Molecular and cellular biochemistry
影响因子:
4.3
作者:
[]
通讯作者:
Remote Hind Limb Ischemia Mechanism of Cardioprotection
-
批准号:10247852
-
项目类别:
-
资助金额:$6.49万
-
财政年份:2020
-
负责人:Suresh C. Tyagi
-
依托单位:
Remote Hind Limb Ischemia Mechanism of Cardioprotection
-
批准号:10215605
-
项目类别:
-
资助金额:$38.5万
-
财政年份:2018
-
负责人:Suresh C. Tyagi
-
依托单位:
Remote Hind Limb Ischemia Mechanism of Cardioprotection
-
批准号:10438112
-
项目类别:
-
资助金额:$10.45万
-
财政年份:2018
-
负责人:Suresh C. Tyagi
-
依托单位:
Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
-
批准号:10357570
-
项目类别:
-
资助金额:$33.54万
-
财政年份:2018
-
负责人:Suresh C. Tyagi
-
依托单位:
Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
-
批准号:10089145
-
项目类别:
-
资助金额:$32.86万
-
财政年份:2018
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负责人:Suresh C. Tyagi
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依托单位:
Mitophagic and anti-angiogenic mechanism of heart failure
-
批准号:8600989
-
项目类别:
-
资助金额:$36.75万
-
财政年份:2011
-
负责人:Suresh C. Tyagi
-
依托单位:
Mitophagic and anti-angiogenic mechanism of heart failure
-
批准号:8258238
-
项目类别:
-
资助金额:$37.38万
-
财政年份:2011
-
负责人:Suresh C. Tyagi
-
依托单位:
Mitophagic and anti-angiogenic mechanism of heart failure
-
批准号:8131312
-
项目类别:
-
资助金额:$37.25万
-
财政年份:2011
-
负责人:Suresh C. Tyagi
-
依托单位:
Mitophagic and anti-angiogenic mechanism of heart failure
-
批准号:8403722
-
项目类别:
-
资助金额:$35.7万
-
财政年份:2011
-
负责人:Suresh C. Tyagi
-
依托单位:
Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
-
批准号:7408062
-
项目类别:
-
资助金额:$37.0万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Mechanisms of Cerebral Vascular Remodeling
-
批准号:7845565
-
项目类别:
-
资助金额:$32.05万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Mechanisms of Cerebral Vascular Remodeling
-
批准号:7315147
-
项目类别:
-
资助金额:$32.38万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Mechanisms of Cerebral Vascular Remodeling
-
批准号:8076171
-
项目类别:
-
资助金额:$31.73万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Mechanisms of Cerebral Vascular Remodeling
-
批准号:7414460
-
项目类别:
-
资助金额:$32.38万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
-
批准号:7797672
-
项目类别:
-
资助金额:$37.0万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
-
批准号:7242879
-
项目类别:
-
资助金额:$37.0万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Mechanisms of Cerebral Vascular Remodeling
-
批准号:7624309
-
项目类别:
-
资助金额:$32.38万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Implications of Endothelial-Myocyte Uncoupling in Cardiac Arrhythmia
-
批准号:7597230
-
项目类别:
-
资助金额:$37.0万
-
财政年份:2007
-
负责人:Suresh C. Tyagi
-
依托单位:
Inhibitor ameliorates oxidative and proteolytic strees
-
批准号:7340811
-
项目类别:
-
资助金额:$9.23万
-
财政年份:2003
-
负责人:Suresh C. Tyagi
-
依托单位:
Inhibitor ameliorates oxidative and proteolytic strees
-
批准号:7015788
-
项目类别:
-
资助金额:$2.32万
-
财政年份:2003
-
负责人:Suresh C. Tyagi
-
依托单位:
海外基金