Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte

星形胶质细胞中转谷氨酰胺酶 2 (TG2) 介导的基因表达机制

基本信息

  • 批准号:
    10293984
  • 负责人:
  • 金额:
    $ 42.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2024-01-31
  • 项目状态:
    已结题

项目摘要

Astrocytes play an indispensable role in maintaining a healthy environment for neuronal function, and in mediating the response of the CNS to injury. Following an injury astrocytes become “reactive” and mediate both helpful and harmful outcomes depending on their gene expression profile. However the molecular mechanisms that regulate gene expression in astrocytes and thus their response to injury has not been fully delineated. One protein that plays a key role in regulating the response of astrocytes to insults is transglutaminase 2 (TG2). Deletion or depletion of TG2 results in astrocytes taking on a more “helpful” phenotype, however the underlying molecular mechanisms are unknown. TG2 is a multifunctional protein; it catalyzes a calcium dependent transamidation reaction, binds and hydrolyzes GTP and can function as a scaffold or linker protein. TG2 undergoes large conformational changes mediated by calcium and GTP binding, and its conformation can dictate its function independent of its enzymatic activities. These conformational states are key a factors in determining cell survival/cell death outcomes. There is a growing awareness that TG2 likely regulates gene expression, however the mechanisms of TG2-mediated regulation of gene expression in astrocytes has not been fully explored. One possible mechanism may be by TG2 interacting with, and modulating the function of, a protein that plays a pivotal role in regulating gene expression. One factor that plays a key role in regulating chromatin accessibility and the activity of specific transcription factors is Zbtb7a. Intriguingly, preliminary data indicate that TG2 interacts with Zbtb7a, and binding sites for these transcription factors are in the majority of pro-survival genes that are upregulated in TG2-/- astrocytes. The UNDERLYING PREMISE of this proposal is that TG2 plays a role in regulating gene expression in astrocytes, and thus how they respond to injury. However, a CRITICAL KNOWLEDGE GAP is how TG2 regulates gene expression. The OVERALL HYPOTHESIS of this application is that TG2, in a conformational dependent manner, moderates chromatin accessibility and the gene expression landscape, which contributes to how astrocytes respond to injury. The NOVELTY of this project is that we will be using an integrated “omic” approach (ATAC-seq, RNA-seq, ChIP-seq) and both in vitro and in vivo models of TG2+/+ and TG2-/- astrocytes to establish the mechanisms by which TG2 in a specific conformation regulates gene expression. The specific aims of this proposal are to test the hypothesis that: (1) the conformation of TG2 play an essential role in determining its ability to regulate chromatin accessibility and gene expression, and (2) TG2 mediates gene expression in astrocytes in part by regulating the function of Zbtb7a. The data generated from these novel and exploratory studies will provide the basis for a future R01 grant application focused on delineating the molecular mechanisms and pathways regulated by TG2 in astrocytes to direct outcomes following CNS injury.
星形胶质细胞在维持神经元功能的健康环境中发挥着不可或缺的作用, 介导CNS对损伤的反应。损伤后,星形胶质细胞变得“反应性”并介导 有益和有害的结果取决于他们的基因表达谱。然而,分子机制 调节星形胶质细胞中基因表达并因此它们对损伤的反应还没有被完全描述。一 在调节星形胶质细胞对损伤的反应中起关键作用的蛋白质是转氨酶2(TG 2)。 TG 2的缺失或消耗导致星形胶质细胞呈现更“有用”的表型,然而, 分子机制尚不清楚。TG 2是一种多功能蛋白质;它催化钙依赖性 通过转酰胺基反应,结合并水解GTP,并可作为支架或接头蛋白发挥作用。TG2 经历由钙和GTP结合介导的大的构象变化,并且其构象可以决定 其功能独立于其酶活性。这些构象状态是决定 细胞存活/细胞死亡结果。越来越多的人意识到TG 2可能调节基因表达, 然而,TG 2介导的星形胶质细胞基因表达调控机制尚未完全阐明, 探讨了一种可能的机制是TG 2与蛋白质相互作用并调节蛋白质的功能 在调节基因表达中起着关键作用。在调节染色质中起关键作用的一个因子 可及性和活性的特异性转录因子是Zbtb 7a。有趣的是,初步数据显示, TG 2与Zbtb 7a相互作用,并且这些转录因子的结合位点大多数是促存活的。 在TG 2-/-星形胶质细胞中上调的基因。该提案的基本前提是,TG 2发挥 在调节星形胶质细胞基因表达中的作用,从而调节它们对损伤的反应。然而,一个关键 了解GAP是TG 2如何调节基因表达。本申请的总体假设 TG 2以构象依赖的方式调节染色质可及性和基因表达 景观,这有助于星形胶质细胞如何应对损伤。这个项目的新奇之处在于,我们将 使用整合的“组学”方法(ATAC-seq,RNA-seq,ChIP-seq)以及体外和体内模型, TG 2 +/+和TG 2-/-星形胶质细胞,以建立特定构象的TG 2调节 基因表达。本研究的具体目的是验证以下假设:(1)TG 2的构象 在决定其调节染色质可及性和基因表达的能力方面发挥重要作用,以及(2) TG 2部分通过调节Zbtb 7a的功能来介导星形胶质细胞中的基因表达。生成的数据 这些新颖的探索性研究将为未来的R 01资助申请提供基础,重点关注 描绘星形胶质细胞中TG 2调节的分子机制和途径,以指导以下结果: CNS损伤。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Deletion of Transglutaminase 2 from Mouse Astrocytes Significantly Improves Their Ability to Promote Neurite Outgrowth on an Inhibitory Matrix.
  • DOI:
    10.3390/ijms24076058
  • 发表时间:
    2023-03-23
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Emerson, Jacen;Delgado, Thomas;Girardi, Peter;Johnson, Gail V. W.
  • 通讯作者:
    Johnson, Gail V. W.
Stabilizing transglutaminase 2 in the open conformation results in reactive astrocytes being more neurosupportive.
将转谷氨酰胺酶 2 稳定在开放构象会导致反应性星形胶质细胞更具神经支持性。
  • DOI:
    10.1101/2024.04.15.589192
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Emerson,Jacen;Delgado,Thomas;Hong,Matthew;Keillor,JeffreyW;Johnson,GailVw
  • 通讯作者:
    Johnson,GailVw
Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury.
  • DOI:
    10.3390/cells10112942
  • 发表时间:
    2021-10-29
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Elahi A;Emerson J;Rudlong J;Keillor JW;Salois G;Visca A;Girardi P;Johnson GVW;Pröschel C
  • 通讯作者:
    Pröschel C
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Gail V. W. Johnson其他文献

Glycogen Synthase Kinase 3β Phosphorylates Tau at Both Primed and Unprimed Sites
糖原合酶激酶 3β 在引发和未引发的位点磷酸化 Tau
Metal-catalyzed oxidation of bovine neurofilaments in vitro.
牛神经丝的体外金属催化氧化。
  • DOI:
  • 发表时间:
    1995
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    Juan C. Troncoso;Anthony C. Costello;James H. Kim;Gail V. W. Johnson
  • 通讯作者:
    Gail V. W. Johnson

Gail V. W. Johnson的其他文献

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{{ truncateString('Gail V. W. Johnson', 18)}}的其他基金

Mitochondrial dysfunction and tau pathology in Alzheimer's disease
阿尔茨海默病中的线粒体功能障碍和 tau 病理学
  • 批准号:
    10805120
  • 财政年份:
    2023
  • 资助金额:
    $ 42.35万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10269305
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10461933
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
BAG3 调节 Rab35 和 ESCRT/内溶酶体途径
  • 批准号:
    10667539
  • 财政年份:
    2021
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10374933
  • 财政年份:
    2020
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10188394
  • 财政年份:
    2020
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau Post-Translational Modifications and Mitochondrial Quality Control
Tau 翻译后修饰和线粒体质量控制
  • 批准号:
    10601125
  • 财政年份:
    2020
  • 资助金额:
    $ 42.35万
  • 项目类别:
Tau protein turnover and mitochondrial stress responses
Tau 蛋白周转和线粒体应激反应
  • 批准号:
    9761421
  • 财政年份:
    2018
  • 资助金额:
    $ 42.35万
  • 项目类别:
The degradation of tau by selective autophagy
选择性自噬降解 tau
  • 批准号:
    9395850
  • 财政年份:
    2017
  • 资助金额:
    $ 42.35万
  • 项目类别:
The degradation of tau by selective autophagy
选择性自噬降解 tau
  • 批准号:
    9918995
  • 财政年份:
    2017
  • 资助金额:
    $ 42.35万
  • 项目类别:

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