Titin in the pregnant uterus – a loss of function approach to smooth muscle biomechanics and mechanosignaling

妊娠子宫中的肌联蛋白 â 平滑肌生物力学和机械信号传导功能丧失的方法

基本信息

项目摘要

Titin is the largest known protein in mammals. Its function has been primarily analyzed in heart and skeletal muscle, where it determines the proper assembly and spacing of the sarcomere - the main contractile unit of striated muscle - as well as the elastic properties of the myofilament. Mutations in the titin gene have been recognized as the most common cause of inherited heart disease.In smooth muscle, researchers have struggled to characterize titin expression, localization, and function. Although preliminary data suggests an interaction with α-actinin and myosin filaments, the role of titin in smooth muscle is only poorly understood.Recently, we have generated smooth muscle specific titin knockout mice and uncovered an embryo implantation defect in deficient mothers. The resulting mislocalization and crowding mimics the phenotype of mice with a defect in the lysophosphatidic acid receptor 3 and phospholipase A2 alpha, which link to G-protein coupled receptor signaling, calcium mobilization, and the arachidonic acid pathway. Accordingly, we propose that smooth muscle titin determines the mechanical, metabolic, and signaling properties of the muscular wall of the uterus. Our preliminary analysis suggests that smooth muscle titin contributes to the peristaltic movement of the pregnant uterus as a prerequisite for proper implantation. Here, we will study the molecular, cellular, and functional basis of the phenotype and characterize smooth muscle titin expression on the RNA and protein level, including its localization and the smooth muscle titin interactome. We will determine the elastic and contractile properties of wildtype and titin-deficient uterus rings and investigate if titin based signaling contributes to the implantation phenotype. The proposed work could provide novel insights into the development of ectopic pregnancies and implantation defects.
Titin是已知的哺乳动物中最大的蛋白质。它的功能主要是在心脏和骨骼肌中分析的,在那里它决定了肌节的适当组装和间距-横纹肌的主要收缩单位-以及肌丝的弹性特性。肌动蛋白基因的突变被认为是遗传性心脏病最常见的原因。在平滑肌领域,研究人员一直在努力研究肌动蛋白的表达、定位和功能。虽然初步数据表明肌动蛋白与α-肌动蛋白和肌球蛋白细丝相互作用,但对肌动蛋白在平滑肌中的作用还知之甚少。最近,我们培育了平滑肌特异性肌动蛋白基因敲除小鼠,并在缺陷母亲中发现了胚胎植入缺陷。由此产生的错误定位和拥挤模仿了溶血磷脂酸受体3和磷脂酶A2α缺陷小鼠的表型,这两个缺陷与G蛋白偶联受体信号、钙动员和花生四烯酸途径有关。因此,我们认为平滑肌肌联蛋白决定了子宫肌壁的机械、代谢和信号特性。我们的初步分析表明,作为正确植入的先决条件,平滑肌肌联蛋白有助于妊娠子宫的蠕动。在这里,我们将研究其表型的分子、细胞和功能基础,并在RNA和蛋白质水平上表征平滑肌titin的表达,包括其定位和平滑肌titin的相互作用组。我们将确定野生型和Titin缺陷型子宫环的弹性和收缩特性,并研究基于Titin的信号是否与植入表型有关。这项拟议的工作可以为宫外孕和植入缺陷的发展提供新的见解。

项目成果

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Professor Dr. Maik Gollasch其他文献

Professor Dr. Maik Gollasch的其他文献

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{{ truncateString('Professor Dr. Maik Gollasch', 18)}}的其他基金

Transient receptor potential vanilloid type 1 (TRPV1) channels in acute kidney injury
急性肾损伤中瞬时受体电位香草酸 1 型 (TRPV1) 通道
  • 批准号:
    192637660
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Units
ADRF, vasoregulation and hypertension
ADRF、血管调节和高血压
  • 批准号:
    193179237
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Molecular Mechanisms of Cerebral Vascular Autoregulation
脑血管自动调节的分子机制
  • 批准号:
    124911428
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
    Research Grants
TRPC6-Kanäle und Niere
TRPC6 通道和肾脏
  • 批准号:
    145880777
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
    Research Grants
ADRF und Regulation der arteriellen Gefäßfunktion
ADRF 和动脉血管功能的调节
  • 批准号:
    5415229
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Bindungsstellen und regulatorische Domänen von spannungsaktivierten Ca2+-Kanälen für Farnesol
法尼醇电压激活 Ca2+ 通道的结合位点和调控域
  • 批准号:
    5275176
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Ca-Sparks und Differenzierung von arteriellen Gefäßmuskelzellen
钙火花与动脉血管肌细胞的分化
  • 批准号:
    5172566
  • 财政年份:
    1999
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Titin in vascular smooth muscle – from scaffold to mechanosensor
血管平滑肌中的肌联蛋白 â 从支架到机械传感器
  • 批准号:
    462843930
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Role of ryanodine receptor Ca2+ channels in adaptative vascular processes
兰尼碱受体 Ca2 通道在适应性血管过程中的作用
  • 批准号:
    318527103
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
TRPC6 and kidney
TRPC6 和肾脏
  • 批准号:
    253158530
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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以PXR、CAR为核心的调控网络、作用机制及其指导环磷酰胺个体化用药的临床转化研究
  • 批准号:
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    2011
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    60.0 万元
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