Decoding protein MARylation networks in astrocytes using chemical biology approaches
使用化学生物学方法解码星形胶质细胞中的蛋白质 MARylation 网络
基本信息
- 批准号:10378049
- 负责人:
- 金额:$ 50.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ADP ribosylationAddressAdenosine Diphosphate RiboseAlzheimer&aposs DiseaseAmino AcidsAreaAstrocytesBacteriaBindingBiologyBrainBrain InjuriesCell Membrane PermeabilityCell physiologyCellsCellular biologyChemicalsChemistryCollaborationsDataDevelopmentEngineeringEnvironmentEnzymesFamilyFamily memberFundingGenerationsGoalsGrowth FactorHealthImmune responseImmune signalingImmunooncologyIndividualInnate Immune ResponseIschemic StrokeKnowledgeLaboratoriesLeadLigandsLiteratureMammalian CellMammalsMasksMass Spectrum AnalysisMediatingMediator of activation proteinMembraneMultiple SclerosisNatural ImmunityNatureNerve DegenerationNervous System TraumaNeuraxisNeurodegenerative DisordersNeurosciencesNicotinamide adenine dinucleotideNucleotidesPathogenesisPathologyPathway interactionsPhenotypePhysiologicalPost-Translational Protein ProcessingProcessProtein EngineeringProteinsRoleShapesSignal TransductionSiteStimulusStructureTestingToxinVariantVirusWorkacute infectionanalogastrogliosiscell typechemical synthesischronic inflammatory diseasedesignhigh riskimmunoregulationimprovedinhibitorinsightknockout genemembermultidisciplinaryneuroinflammationnovelnovel therapeutic interventionpathogenresponsespatiotemporalsteroid hormonetandem mass spectrometrytool
项目摘要
Project Summary
Astrocytes are critical regulators of innate immunity in the central nervous system (CNS). Stimulation of CNS
innate immunity by neuroinflammatory activators such as pathogens and brain injury, as well as in response to
neurodegeneration, cause astrocytes to undergo a transition to a reactive phenotype called astrogliosis. While it
is well accepted that astrogliosis can act as a protective mechanism to minimize CNS damage, the mechanisms
that regulate astrogliosis are not well understood. Our preliminary results and data from the literature support
our general hypothesis that PARP7 controlled MARylation critically shapes the innate immune responses in
the CNS. Our long-term goal is to understand the role of PARP7 in astrogliosis and whether PARP7 represents
an actionable target for CNS pathologies that arise as a consequence of activation of CNS innate immunity. The
objective of the proposed work is elucidate the mechanisms by which PARP7 regulates innate immunity in
astrocytes. PARP7 has emerged as a critically important member of a large enzyme family known as PARPs,
especially in the innate immune response. Similar to other PARP family members, PARP7 catalyzes the post-
translational modification known as mono-ADP-ribosylation (MARylation), which involves the transfer of
ADP-ribose from NAD+ to amino acids on target proteins. The MARylation targets of PARP7 in astrocytes are
unknown. To decode the mechanisms by which PARP7 regulates innate immunity in astrocyte, we need to
identify the direct targets of PARP7 in astrocytes. Identifying the direct targets of PARP7 has been challenging,
however, due to the fact that PARPs share the same substrate NAD+. To overcome this limitation, we describe
the development of engineered PARP7—orthogonal NAD+ analogue pairs for identifying the direct targets of
PARP7 in astrocytes lysates (Aim I). We also describe the generation of membrane-permeant variants of our
orthogonal NAD+ analogues, which are critical for identifying PARP7 targets in intact astrocytes using stimuli
that activate the innate immune response in astrocytes (Aim II). Lastly, we describe a strategy for improving
the selectivity of PARP7 inhibitors (Aim III). Selective inhibitors of PARP7 are essential chemical probes for
evaluating the function of PARP7-mediated MARylation in the innate immune response in astrocytes. We
anticipate that these studies will not only clarify our understanding of the function of PARP7-mediated
MARylation in innate immunity in astrocytes, but could also lead to new therapeutic strategies for CNS
pathologies, particularly neuroinflammatory (e.g. multiple sclerosis) and neurodegenerative diseases (e.g.
Alzheimer's disease). More generally, the results obtained from these studies will have far-reaching impact on our
understanding of MARylation in cell signaling.
项目概要
星形胶质细胞是中枢神经系统(CNS)先天免疫的关键调节因子。刺激中枢神经系统
病原体和脑损伤等神经炎症激活剂的先天免疫,以及对
神经变性,导致星形胶质细胞转变为称为星形胶质细胞增生的反应性表型。虽然它
人们普遍认为,星形胶质细胞增生可以作为一种保护机制,最大限度地减少中枢神经系统损伤,该机制
调节星形胶质细胞增生的机制尚不清楚。我们的初步结果和文献数据支持
我们的一般假设是 PARP7 控制的 MARylation 关键地塑造了先天免疫反应
中枢神经系统。我们的长期目标是了解 PARP7 在星形胶质细胞增生中的作用以及 PARP7 是否代表
由于中枢神经系统先天免疫激活而产生的中枢神经系统病理的可操作目标。这
拟议工作的目标是阐明 PARP7 调节先天免疫的机制
星形胶质细胞。 PARP7 已成为 PARPs 大酶家族中极其重要的成员,
尤其是在先天免疫反应中。与其他 PARP 家族成员类似,PARP7 催化后
翻译修饰称为单 ADP 核糖基化 (MARylation),其中涉及转移
ADP-核糖从 NAD+ 转化为靶蛋白上的氨基酸。星形胶质细胞中 PARP7 的 MARylation 靶点是
未知。为了解码 PARP7 调节星形胶质细胞先天免疫的机制,我们需要
确定星形胶质细胞中 PARP7 的直接靶标。确定 PARP7 的直接目标一直具有挑战性,
然而,由于 PARP 共享相同的底物 NAD+。为了克服这个限制,我们描述
工程化 PARP7 的开发——正交 NAD+ 类似物对,用于识别直接靶标
星形胶质细胞裂解物中的 PARP7(目标 I)。我们还描述了我们的膜渗透变体的产生
正交 NAD+ 类似物,对于使用刺激识别完整星形胶质细胞中的 PARP7 靶标至关重要
激活星形胶质细胞的先天免疫反应(目标 II)。最后,我们描述了改进策略
PARP7 抑制剂的选择性(目标 III)。 PARP7 的选择性抑制剂是重要的化学探针
评估 PARP7 介导的 MARylation 在星形胶质细胞先天免疫反应中的功能。我们
预计这些研究不仅会澄清我们对 PARP7 介导的功能的理解
星形胶质细胞先天免疫中的 MARylation 也可能导致中枢神经系统的新治疗策略
病理学,特别是神经炎症(例如多发性硬化症)和神经退行性疾病(例如神经退行性疾病)
阿尔茨海默病)。更一般地说,这些研究获得的结果将对我们产生深远的影响。
了解细胞信号转导中的 MARylation。
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)
专利数量(1)
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Michael S Cohen其他文献
The significance of mast cells in basal cell carcinoma.
肥大细胞在基底细胞癌中的意义。
- DOI:
- 发表时间:
1995 - 期刊:
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- 作者:
Michael S Cohen;Gary S. Rogers - 通讯作者:
Gary S. Rogers
NON-CLAMPED, NON-ISCHEMIC PARTIAL NEPHRECTOMY: THE NEW GOLD STANDARD
- DOI:
10.1016/s0022-5347(08)61400-7 - 发表时间:
2008-04-01 - 期刊:
- 影响因子:
- 作者:
Teodora Kurteva;Michael S Cohen;Gjanje L Smith;John A Libertino - 通讯作者:
John A Libertino
THE QUEST TO FIND HIGH GRADE PROSTATE CANCER: ARE WE FAILING?
- DOI:
10.1016/s0022-5347(08)60430-9 - 发表时间:
2008-04-01 - 期刊:
- 影响因子:
- 作者:
Sarah Fitch;Michael S Cohen;Robin Ruthazer;John A Libertino - 通讯作者:
John A Libertino
AI Model Versus Clinician Otoscopy in the Operative Setting for Otitis Media Diagnosis.
AI 模型与临床医生耳镜检查在中耳炎诊断手术中的比较。
- DOI:
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2023 - 期刊:
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- 作者:
Krish Suresh;Michael P Wu;Fouzi Benboujja;Barbara Christakis;Alice Newton;Christopher J. Hartnick;Michael S Cohen - 通讯作者:
Michael S Cohen
Reward enhancement of item-location associative memory spreads to similar items within a category.
项目位置关联记忆的奖励增强会扩散到类别内的相似项目。
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2024 - 期刊:
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- 作者:
Evan Grandoit;Michael S Cohen;Paul J. Reber - 通讯作者:
Paul J. Reber
Michael S Cohen的其他文献
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{{ truncateString('Michael S Cohen', 18)}}的其他基金
Identifying the molecular target for macrophage activation by chlorpyrifos
确定毒死蜱激活巨噬细胞的分子靶标
- 批准号:
10555298 - 财政年份:2022
- 资助金额:
$ 50.3万 - 项目类别:
Identifying the targets of virus-induced PARPs during SARS-CoV-2 infection
识别 SARS-CoV-2 感染期间病毒诱导的 PARP 的靶标
- 批准号:
10573499 - 财政年份:2022
- 资助金额:
$ 50.3万 - 项目类别:
Identifying the molecular target for macrophage activation by chlorpyrifos
确定毒死蜱激活巨噬细胞的分子靶标
- 批准号:
10467360 - 财政年份:2022
- 资助金额:
$ 50.3万 - 项目类别:
Decoding protein MARylation networks in astrocytes using chemical biology approaches
使用化学生物学方法解码星形胶质细胞中的蛋白质 MARylation 网络
- 批准号:
10599222 - 财政年份:2014
- 资助金额:
$ 50.3万 - 项目类别:
Decoding protein ADP-ribosylation networks in neurons using a chemical genetic ap
使用化学遗传 ap 解码神经元中的蛋白质 ADP-核糖基化网络
- 批准号:
9272745 - 财政年份:2014
- 资助金额:
$ 50.3万 - 项目类别:
Decoding protein ADP-ribosylation networks in neurons using a chemical genetic ap
使用化学遗传 ap 解码神经元中的蛋白质 ADP-核糖基化网络
- 批准号:
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