Tubulin modifications and cytoskeletal alterations in aging

衰老过程中的微管蛋白修饰和细胞骨架变化

基本信息

项目摘要

Project Summary Remarkably, our understanding of the mechanisms that lead to cytoskeletal alterations and the phenotypic impact of these alterations in aging cells remains very limited. We have identified and begun characterizing key proteins required to maintain normal nuclear morphology, including two novel proteins (LRRC49 and C11orf49) that assemble into a tubulin poly-glutamylase (TPG) complex. We have recently shown that each protein regulates both tubulin glutamylation and nuclear morphology, and ablation of these genes alters post- translational modifications (PTM) of tubulin, cytoskeletal networks, and nuclear shape. Since similar cytoskeletal and nuclear defects are also observed in cells obtained from patients with the premature aging syndrome, Hutchinson-Gilford progeria syndrome (HGPS), this prompted us to hypothesize that specific defects in PTMs and microtubule networks could be associated with aging. Furthermore, it is known that levels of SUN1, a component of the LINC (Linkers of Nucleoskeleton and Cytoskeleton) complex that connects the cytoskeleton and the nucleoskeleton, are altered during normal and premature aging. However, it is unknown whether altered SUN1 levels are a cause or consequence of aging. We will pursue two Aims that combine biochemical and cell biological approaches to (1) investigate a global role for defects in microtubule networks and alterations in tubulin glutamylation and SUN1 levels during physiological aging and in progeroid cells, and (2) identify how defects associated with normal and premature aging are translated into genome-wide changes in chromatin topology. Here, we will specifically focus on how the TPG and SUN1 protein globally regulate microtubule networks and nuclear assembly during aging. Our studies will address fundamental questions related to the role of SUN1 and tubulin modifications in nuclear shape changes and in physiological and pathological models of aging, and our studies will determine whether these alterations are a cause or consequence of aging. Our studies will also provide insights into the changes in chromatin topology sustained by cells that age through normal or pathological mechanisms.
项目概要 值得注意的是,我们对导致细胞骨架改变和表型的机制的理解 这些改变对衰老细胞的影响仍然非常有限。我们已经确定并开始表征关键 维持正常核形态所需的蛋白质,包括两种新蛋白质(LRRC49 和 C11orf49) 组装成微管蛋白聚谷氨酰胺酶 (TPG) 复合物。我们最近表明,每种蛋白质 调节微管蛋白谷氨酰化和核形态,这些基因的消融会改变后 微管蛋白、细胞骨架网络和核形状的翻译修饰 (PTM)。既然类似 在从早衰患者身上获得的细胞中也观察到细胞骨架和细胞核缺陷 综合症,哈钦森-吉尔福德早衰综合症(HGPS),这促使我们假设特定的 PTM 和微管网络的缺陷可能与衰老有关。此外,众所周知,水平 SUN1 是 LINC(核骨架和细胞骨架连接器)复合物的一个组成部分,连接 细胞骨架和核骨架在正常和过早衰老过程中都会发生改变。然而,尚不清楚 SUN1 水平的改变是否是衰老的原因或结果。我们将追求两个目标相结合 生化和细胞生物学方法(1)研究微管网络缺陷的整体作用 以及生理衰老期间和早衰细胞中微管蛋白谷氨酰化和 SUN1 水平的变化,以及 (2) 确定与正常和过早衰老相关的缺陷如何转化为全基因组变化 在染色质拓扑结构中。在这里,我们将特别关注TPG和SUN1蛋白如何全局调节 衰老过程中的微管网络和核组装。我们的研究将解决基本问题 与 SUN1 和微管蛋白修饰在核形状变化以及生理和功能中的作用有关 衰老的病理模型,我们的研究将确定这些变化是原因还是衰老 衰老的后果。我们的研究还将深入了解染色质拓扑结构持续的变化 由通过正常或病理机制老化的细胞引起。

项目成果

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Brian D Dynlacht其他文献

Brian D Dynlacht的其他文献

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{{ truncateString('Brian D Dynlacht', 18)}}的其他基金

Exploring networks underlying muscle stem cell identity - Resubmission - 1
探索肌肉干细胞身份背后的网络 - 重新提交 - 1
  • 批准号:
    10627924
  • 财政年份:
    2021
  • 资助金额:
    $ 25.43万
  • 项目类别:
Exploring networks underlying muscle stem cell identity - Resubmission - 1
探索肌肉干细胞身份背后的网络 - 重新提交 - 1
  • 批准号:
    10406897
  • 财政年份:
    2021
  • 资助金额:
    $ 25.43万
  • 项目类别:
Exploring networks underlying muscle stem cell identity - Resubmission - 1
探索肌肉干细胞身份背后的网络 - 重新提交 - 1
  • 批准号:
    10116803
  • 财政年份:
    2021
  • 资助金额:
    $ 25.43万
  • 项目类别:
Restoring ciliogenesis as a novel approach to blocking breast cancer growth
恢复纤毛发生作为阻止乳腺癌生长的新方法
  • 批准号:
    9292934
  • 财政年份:
    2017
  • 资助金额:
    $ 25.43万
  • 项目类别:
Regulation of myogenic transcription by the Paf1C complex
Paf1C 复合物对肌源性转录的调节
  • 批准号:
    9537650
  • 财政年份:
    2017
  • 资助金额:
    $ 25.43万
  • 项目类别:
Epigenomic regulation in skeletal muscle cells and their precursors
骨骼肌细胞及其前体细胞的表观基因组调控
  • 批准号:
    9174484
  • 财政年份:
    2016
  • 资助金额:
    $ 25.43万
  • 项目类别:
pRB and changes in the chromatin landscape during myogenic differentiation
pRB 和生肌分化过程中染色质景观的变化
  • 批准号:
    8665617
  • 财政年份:
    2014
  • 资助金额:
    $ 25.43万
  • 项目类别:
The Role of pRB and Co-repressors in Transcriptional Regulation
pRB 和辅阻遏物在转录调控中的作用
  • 批准号:
    8764196
  • 财政年份:
    2013
  • 资助金额:
    $ 25.43万
  • 项目类别:
The Role of pRB and Co-repressors in Transcriptional Regulation
pRB 和辅阻遏物在转录调控中的作用
  • 批准号:
    8761281
  • 财政年份:
    2013
  • 资助金额:
    $ 25.43万
  • 项目类别:
The Role of CP110 in Ciliogenesis
CP110 在纤毛发生中的作用
  • 批准号:
    8663546
  • 财政年份:
    2013
  • 资助金额:
    $ 25.43万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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研究肌动蛋白和微管如何协调及其相关性。
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