Role of titin in the pathophysiology of diaphragm weakness during mechanical vent
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
基本信息
- 批准号:8614046
- 负责人:
- 金额:$ 37.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAnimalsAntibodiesApplications GrantsAtrophicBinding ProteinsBiophysicsBiopsyBreathingClinicalDataDenervationDevelopmentEnvironmental air flowFailureFiberFunctional disorderGene TargetingGenetic EngineeringGoalsGrowthHourHumanHypertrophyIntensive Care UnitsLeadLinkLocationLungLung diseasesMechanical StressMechanical ventilationMechanicsMediatingMicrofilamentsModelingMolecularMorphologyMusMuscleMutationOxygenPatientsPilot ProjectsPlayPropertyProteinsRNA Recognition MotifRNA SplicingRattusResearchRespirationRespiratory DiaphragmRoentgen RaysRoleSignal PathwaySignal TransductionStretchingStructureTestingTimeVentWeaningWorkX ray diffraction analysisX-Ray Diffractionbaseconnectininnovationlink proteinmortalitymouse modelmuscle formnovelnovel therapeuticspreconditioningprotein degradationpublic health relevanceresponsesensortooluptake
项目摘要
7. Summary.
The long-term goal of this proposal is to gain detailed understanding of how the diaphragm - the main muscle
of respiration - rapidly weakens in response to mechanical unloading and of the mechanisms whereby the
giant elastic protein titin influences this response.
The diaphragm is a unique muscle in that it is constantly subjected to mechanical loading. Recent work
suggests that diaphragm strength is remarkably sensitive to mechanical unloading, as occurs during
mechanical ventilation in the ICU. How unloading affects diaphragm strength is poorly understood. Increasing
this understanding is critically important: within hours, diaphragm unloading during mechanical ventilation
causes diaphragm weakness in ICU patients, which leads to difficulties in weaning patients from ventilatory
support and contributes to mortality. The search for the molecular triggers for the development of diaphragm
weakness during mechanical unloading is ongoing. The potential role of mechanosensor proteins, that link
diaphragm unloading to protein turnover, is unexplored but is an exciting and novel concept that needs to be
studied. A candidate mechanosensor is titin, a giant elastic protein that has been suggested to sense
mechanical stress and link this to trophic signalling pathways. The elucidation of titin's role in diaphragm
trophicity and in diaphragm weakness during mechanical ventilation is central to this grant proposal.
Aim 1 will critically test whether titin affects muscle trophicity. I will use unilateral diaphragm denervation
(UDD), a condition that is clinically important and that presents itself as a great tool for this work as it induces
rapid hypertrophy of the denervated hemidiaphragm due to cyclic passive stretch. I will study UDD in two novel
titin KO mouse models: one in which titin stiffness is increased through deletion of Ig domains (Ig KO) and
another in which titin stiffness is decreased through deletion of the titin splice factor rbm20 (Rbm20 KO). I
anticipate that the hypertrophic response following UDD is exaggerated in Ig KO mice and blunted in Rmb20
KO mice, and that this response is mediated by altered titin signaling. Aim 2 will study whether low titin
stiffness protects the diaphragm from weakening during mechanical ventilation-induced unloading and will use
a rat model with low titin stiffness. If titin-based mechanosensing mediates the response of the diaphragm to
mechanical unloading, then I anticipate that low titin stiffness, by preconditioning the diaphragm to reduced
mechanosensing, blunts this response. Aim 3 will study the mechanistic basis for diaphragm weakness in
mechanically ventilated ICU patients using, for the first time, diaphragm fibers isolated from biopsies of
mechanically ventilated ICU patients. The goal is to investigate whether the findings of animal studies
extrapolate to patients.
The innovation of this proposal lies in the novel research foci with innovative guiding hypotheses, its novel
mouse models, unique diaphragm biopsies from mechanically ventilated ICU patients, and its novel
experimental tools. The proposal's integrative approach is expected to lead to a significant step forward in
our understanding of diaphragm function and the role of titin therein.
7.摘要
这项提案的长期目标是详细了解横隔膜-主要肌肉
呼吸-迅速减弱响应机械卸载和机制,
巨大的弹性蛋白肌联蛋白影响这种反应。
横膈膜是一种独特的肌肉,因为它不断受到机械负荷。最近的工作
表明,隔膜强度是非常敏感的机械卸载,如发生在
重症监护室的机械通气卸载如何影响隔膜强度知之甚少。增加
这一理解至关重要:在数小时内,机械通气期间隔膜卸载
导致ICU患者的膈肌无力,导致患者难以脱离呼吸机,
支持和促进死亡率。寻找膈肌发育的分子触发因素
机械卸载过程中的弱点正在持续。机械传感器蛋白的潜在作用,
隔膜卸载蛋白质周转,是未经探索的,但这是一个令人兴奋的和新颖的概念,需要
研究了一个候选的机械传感器是肌联蛋白,一种巨大的弹性蛋白,
机械应力并将其与营养信号通路联系起来。肌联蛋白在膈肌中的作用
营养性和机械通气期间横膈膜虚弱是这项资助提案的核心。
目的1将严格测试肌联蛋白是否影响肌肉营养。我会用单侧膈肌去神经术
(UDD),这种情况在临床上很重要,并且由于它引起了
由于周期性被动牵拉导致的去神经支配的半侧膈肌快速肥大。我将在两部小说中研究UDD
肌联蛋白KO小鼠模型:其中肌联蛋白刚度通过缺失IG结构域而增加(IG KO),
另一种是通过缺失肌联蛋白剪接因子rbm 20(Rbm 20 KO)降低肌联蛋白刚度。我
预计UDD后的肥大反应在IG KO小鼠中会被夸大,而在Rmb 20中会减弱
KO小鼠,并且这种反应是由改变的肌联蛋白信号传导介导的。目标2将研究低滴度是否
刚度保护隔膜在机械通风引起的卸载期间不被削弱,
具有低肌联蛋白刚度的大鼠模型。如果基于肌联蛋白的机械感测介导隔膜的响应,
机械卸载,那么我预计,低titin刚度,通过预处理隔膜,以减少
机械感应减弱了这种反应。目的3将研究膈肌无力的机制基础,
机械通气ICU患者首次使用从活检组织中分离的隔膜纤维,
机械通气ICU患者。目的是调查动物研究的结果是否
外推到患者身上。
该方案的创新之处在于提出了新的研究重点,提出了新的指导假设,
小鼠模型,机械通气ICU患者的独特隔膜活检,及其新的
实验工具该提案的综合办法预计将导致在以下方面向前迈出重要一步:
我们对横膈膜功能和肌联蛋白在其中的作用的理解。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Coen Ottenheijm其他文献
Coen Ottenheijm的其他文献
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{{ truncateString('Coen Ottenheijm', 18)}}的其他基金
Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
- 批准号:
9816870 - 财政年份:2014
- 资助金额:
$ 37.12万 - 项目类别:
Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
- 批准号:
10659578 - 财政年份:2014
- 资助金额:
$ 37.12万 - 项目类别:
Role of titin in the pathophysiology of diaphragm weakness during mechanical vent
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
- 批准号:
8982039 - 财政年份:2014
- 资助金额:
$ 37.12万 - 项目类别:
Role of titin in the pathophysiology of diaphragm weakness during mechanical vent
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
- 批准号:
9199443 - 财政年份:2014
- 资助金额:
$ 37.12万 - 项目类别:
Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
- 批准号:
10252782 - 财政年份:2014
- 资助金额:
$ 37.12万 - 项目类别:
Role of titin in the pathophysiology of diaphragm weakness during mechanical ventilation
肌联蛋白在机械通气期间膈肌无力病理生理学中的作用
- 批准号:
10438849 - 财政年份:2014
- 资助金额:
$ 37.12万 - 项目类别:
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