Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte
批准号:
10293984
负责人:
Gail V. W. Johnson
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
项目状态:
已结题
起止时间:
2021-08-01 至 2024-01-31
关键词:
ATAC-seqAffectApplications GrantsAstrocytesAttenuatedAwarenessBindingBinding SitesBiologyCalciumCalcium BindingCell DeathCell SurvivalChIP-seqChimeric ProteinsChromatinCo-ImmunoprecipitationsDNA BindingDataDeletion MutagenesisEnvironmentFutureGTP BindingGene ExpressionGene Expression ProfileGene Expression RegulationGenesGenomicsGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHealthIn VitroIndividualInjuryKnowledgeLabelLinkMediatingMolecularMolecular ConformationMusNeuraxisNeuronsOutcomePathway interactionsPharmaceutical PreparationsPhenocopyPhenotypePlayProcessProteinsReactionRecoveryRegulationResistanceRoleSignal TransductionTechniquesTestingWild Type Mousebasecentral nervous system injurydecorinhigh resolution imagingin vivo Modelinhibitor/antagonistmutantnext generationnovelresponseresponse to injuryscaffoldtransamidasestranscription factortranscriptometranscriptome sequencingtransglutaminase 2whole genome
中文摘要
星形胶质细胞在维持神经元功能的健康环境中起着不可或缺的作用
英文摘要
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.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/ijms24076058
发表时间:
2023-03-23
期刊:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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:
bioRxiv : the preprint server for biology
影响因子:
--
作者:
[Emerson,Jacen, Delgado,Thomas, Hong,Matthew, Keillor,JeffreyW, Johnson,GailVw]
通讯作者:
Johnson,GailVw
DOI:
10.3390/cells10112942
发表时间:
2021-10-29
期刊:
Cells
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
Mitochondrial dysfunction and tau pathology in Alzheimer's disease
-
批准号:10805120
-
项目类别:
-
资助金额:$42.35万
-
财政年份:2023
-
负责人:Gail V. W. Johnson
-
依托单位:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
-
批准号:10269305
-
项目类别:
-
资助金额:$43.63万
-
财政年份:2021
-
负责人:Gail V. W. Johnson
-
依托单位:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
-
批准号:10461933
-
项目类别:
-
资助金额:$43.63万
-
财政年份:2021
-
负责人:Gail V. W. Johnson
-
依托单位:
BAG3 regulates Rab35 and the ESCRT/endolysosome pathway
-
批准号:10667539
-
项目类别:
-
资助金额:$43.63万
-
财政年份:2021
-
负责人:Gail V. W. Johnson
-
依托单位:
Tau Post-Translational Modifications and Mitochondrial Quality Control
-
批准号:10374933
-
项目类别:
-
资助金额:$57.09万
-
财政年份:2020
-
负责人:Gail V. W. Johnson
-
依托单位:
Tau Post-Translational Modifications and Mitochondrial Quality Control
-
批准号:10188394
-
项目类别:
-
资助金额:$57.09万
-
财政年份:2020
-
负责人:Gail V. W. Johnson
-
依托单位:
Tau Post-Translational Modifications and Mitochondrial Quality Control
-
批准号:10601125
-
项目类别:
-
资助金额:$57.09万
-
财政年份:2020
-
负责人:Gail V. W. Johnson
-
依托单位:
Tau protein turnover and mitochondrial stress responses
-
批准号:9761421
-
项目类别:
-
资助金额:$23.1万
-
财政年份:2018
-
负责人:Gail V. W. Johnson
-
依托单位:
The degradation of tau by selective autophagy
-
批准号:9395850
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2017
-
负责人:Gail V. W. Johnson
-
依托单位:
The degradation of tau by selective autophagy
-
批准号:9918995
-
项目类别:
-
资助金额:$39.68万
-
财政年份:2017
-
负责人:Gail V. W. Johnson
-
依托单位:
The attenuation of ischemic injury by transglutaminase 2
-
批准号:8652526
-
项目类别:
-
资助金额:$2.57万
-
财政年份:2013
-
负责人:Gail V. W. Johnson
-
依托单位:
Autophagy, p62 and the Nrf2 Intersect to Protect Against Tau Toxicity
-
批准号:8463265
-
项目类别:
-
资助金额:$18.64万
-
财政年份:2012
-
负责人:Gail V. W. Johnson
-
依托单位:
Autophagy, p62 and the Nrf2 Intersect to Protect Against Tau Toxicity
-
批准号:8369614
-
项目类别:
-
资助金额:$23.18万
-
财政年份:2012
-
负责人:Gail V. W. Johnson
-
依托单位:
The attenuation of ischemic injury by transglutaminase 2
-
批准号:8184138
-
项目类别:
-
资助金额:$33.74万
-
财政年份:2011
-
负责人:Gail V. W. Johnson
-
依托单位:
The attenuation of ischemic injury by transglutaminase 2
-
批准号:8401144
-
项目类别:
-
资助金额:$32.61万
-
财政年份:2011
-
负责人:Gail V. W. Johnson
-
依托单位:
The attenuation of ischemic injury by transglutaminase 2
-
批准号:8603292
-
项目类别:
-
资助金额:$38.54万
-
财政年份:2011
-
负责人:Gail V. W. Johnson
-
依托单位:
The attenuation of ischemic injury by transglutaminase 2
-
批准号:8260315
-
项目类别:
-
资助金额:$33.8万
-
财政年份:2011
-
负责人:Gail V. W. Johnson
-
依托单位:
Posttranslational processing of tau: function & dysfunc.
-
批准号:6897351
-
项目类别:
-
资助金额:$26.86万
-
财政年份:2005
-
负责人:Gail V. W. Johnson
-
依托单位:
Core--Molecular detection
-
批准号:7090250
-
项目类别:
-
资助金额:$20.36万
-
财政年份:2005
-
负责人:Gail V. W. Johnson
-
依托单位:
Posttranslational processing of tau: function & dysfunc.
-
批准号:7454783
-
项目类别:
-
资助金额:$12.45万
-
财政年份:2005
-
负责人:Gail V. W. Johnson
-
依托单位:
海外基金