Cadherin-Dependent Regulation of Satellite Cell Function

卫星细胞功能的钙粘蛋白依赖性调节

基本信息

项目摘要

Skeletal muscle has remarkable capacity for regeneration. This capability derives from resident muscle stem cells, called satellite cells (SCs). During adult muscle homeostasis, SCs are quiescent. Upon injury, they are “activated” to generate myoblasts for muscle repair. SCs are localized between myofibers and their surround- ding basal lamina; this niche promotes SC quiescence. Proper regulation of quiescence is necessary for long- term SC function and for successful engraftment of SCs. Therefore, knowledge of how the niche promotes quiescence is critical to harnessing SCs for therapeutic purposes. However, the mechanisms that underlie SC quiescence and the quiescence-to-activation (Q-to-A) transition remain poorly understood. In uninjured muscles in vivo, SCs have long projections. Little is known of these structures, as they are lost during prepara- tion of SCs for study in vitro. We have developed a single myofiber isolation procedure that allows mainten- ance of projections. QSC projections are microtubule (MT)-rich and ringed with cortical F-actin, resembling neuronal axons. Our findings indicate that SC projections are motile, potentially allowing QSCs to scan the surface of the myofiber for damage and/or signals that regulate quiescence vs. activation. Retraction of project- tions occurs upon SC activation and is a very early step in the Q-to-A transition, preceding other known early steps. Cadherins, which are required for quiescence and regulate the Q-to-A transition, are important factors for maintenance of projections. We hypothesize that SC quiescence is a dynamic state, characterized by motile projections regulated by cadherins and the cytoskeleton. We have identified novel factors as candidate regulators of this process, including the GTPase, Rac1; the MT minus-end binding protein, CAMSAP3; and the RhoA GEF, LFC. We will test our hypotheses with a combination of genetic studies in mice and cell biological studies with single myofiber preparations. The following aims are proposed: 1) to determine the roles of Rac1, CAMSAP3, and LFC on SC quiescence and Q-to-A transition, we will construct mice conditionally lacking these factors in adult SCs and assess SC homeostasis, function, and structure in vivo and on single myofibers prepared with our new methods; and 2) to investigate cytoskeletal dynamics of retracting SC projections during the Q-to-A transition, we will adapt live imaging protocols to our single myofiber preparations. Mice with SC- specific expression of fluorescent probes for F-actin and MT dynamics will be employed with time-lapse micro- scopy. The effects of perturbing cadherins, the cytoskeleton, and specific signaling proteins on this initial step of SC activation will be determined. The ability to exploit SCs in muscle therapies requires detailed molecular and cell biological knowledge of SC quiescence and the Q-to-A transition, but they are poorly understood. The proposed aims are highly novel and involve a synergistic combination of genetic and cell biological analyses. They are expected to provide fundamental new information on SC biology. They are therefore anticipated to have a significant impact on the potential use of SCs as therapeutic agents in regenerative medicine.
骨骼肌具有显著的再生能力。这种能力来源于常驻肌干

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Robert S. Krauss其他文献

Alcohol-induced holoprosencephaly (HPE) in Cdo−/− mice: A model for gene–environment interactions
  • DOI:
    10.1016/j.ydbio.2009.05.217
  • 发表时间:
    2009-07-15
  • 期刊:
  • 影响因子:
  • 作者:
    Mingi Hong;Wei Zhang;Robert S. Krauss
  • 通讯作者:
    Robert S. Krauss
Prostaglandin H synthase-dependent co-oxygenation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene in hamster trachea and human bronchus explants.
仓鼠气管和人支气管外植体中 (l-)-7,8-二羟基-7,8-二氢苯并[a]芘的前列腺素 H 合酶依赖性共氧化。
  • DOI:
  • 发表时间:
    1984
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Gregory A. Reed;Roland C. Grafström;Robert S. Krauss;Herman Autrup;Thomas E. Eling
  • 通讯作者:
    Thomas E. Eling
Embracing change: striated-for-smooth muscle replacement in esophagus development
  • DOI:
    10.1186/s13395-016-0099-1
  • 发表时间:
    2016-08-08
  • 期刊:
  • 影响因子:
    4.400
  • 作者:
    Robert S. Krauss;Daisuke Chihara;Anthony I. Romer
  • 通讯作者:
    Anthony I. Romer

Robert S. Krauss的其他文献

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{{ truncateString('Robert S. Krauss', 18)}}的其他基金

Cadherin-Dependent Regulation of Satellite Cell Function
卫星细胞功能的钙粘蛋白依赖性调节
  • 批准号:
    9160344
  • 财政年份:
    2016
  • 资助金额:
    $ 56.97万
  • 项目类别:
Cadherin-Dependent Regulation of Satellite Cell Function
卫星细胞功能的钙粘蛋白依赖性调节
  • 批准号:
    10451802
  • 财政年份:
    2016
  • 资助金额:
    $ 56.97万
  • 项目类别:
Cadherin-Dependent Regulation of Satellite Cell Function
卫星细胞功能的钙粘蛋白依赖性调节
  • 批准号:
    10649727
  • 财政年份:
    2016
  • 资助金额:
    $ 56.97万
  • 项目类别:
Molecular and Developmental Analysis of Holoprosencephaly
前脑无裂畸形的分子和发育分析
  • 批准号:
    10647779
  • 财政年份:
    2015
  • 资助金额:
    $ 56.97万
  • 项目类别:
Molecular and Developmental Analysis of Holoprosencephaly
前脑无裂畸形的分子和发育分析
  • 批准号:
    9107837
  • 财政年份:
    2015
  • 资助金额:
    $ 56.97万
  • 项目类别:
Molecular and Developmental Analysis of Holoprosencephaly
前脑无裂畸形的分子和发育分析
  • 批准号:
    9306018
  • 财政年份:
    2015
  • 资助金额:
    $ 56.97万
  • 项目类别:
Interactions between Shh pathway regulators and fetal alcohol exposure in mice
Shh 通路调节因子与小鼠胎儿酒精暴露之间的相互作用
  • 批准号:
    8318752
  • 财政年份:
    2009
  • 资助金额:
    $ 56.97万
  • 项目类别:
Interactions between Shh pathway regulators and fetal alcohol exposure in mice
Shh 通路调节因子与小鼠胎儿酒精暴露之间的相互作用
  • 批准号:
    8516408
  • 财政年份:
    2009
  • 资助金额:
    $ 56.97万
  • 项目类别:
Interactions between Shh pathway regulators and fetal alcohol exposure in mice
Shh 通路调节因子与小鼠胎儿酒精暴露之间的相互作用
  • 批准号:
    7938761
  • 财政年份:
    2009
  • 资助金额:
    $ 56.97万
  • 项目类别:
Making Muscle in the Embryo and Adult
在胚胎和成人中形成肌肉
  • 批准号:
    7673154
  • 财政年份:
    2009
  • 资助金额:
    $ 56.97万
  • 项目类别:

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神经元的非典型微管生成机制驱动树突和轴突的发育和再生
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