The role of a novel AIF-associated nuclease PAAN1 in neuronal injury
新型 AIF 相关核酸酶 PAAN1 在神经元损伤中的作用
基本信息
- 批准号:8441224
- 负责人:
- 金额:$ 9.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-15 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAmino AcidsAnimal ModelBindingBioinformaticsBiological AssayCatalytic DomainCause of DeathCell DeathCell NucleusCell SurvivalCerebral InfarctionCessation of lifeCorpus striatum structureDNADNA DamageDNA FragmentationDNA RepairDNA biosynthesisDataDependovirusDiseaseEducational process of instructingEnzymesEpigenetic ProcessExonucleaseGenomicsGlutamatesGoalsGrantHela CellsHistone H3HistonesHumanHuman bodyIn VitroInstitutesIschemic Neuronal InjuryKnock-outKnockout MiceLabelLaboratoriesMapsMediatingMentorsModelingMolecularMorbidity - disease rateNamesNeurologicNeurologic DysfunctionsNeuronal InjuryNeuronsNuclearNuclear TranslocationPatientsPhasePlayPoly(ADP-ribose) PolymerasesPost-Translational Protein ProcessingProtein MicrochipsProtein-Arginine N-MethyltransferaseProteinsQuality of lifeRecruitment ActivityResearchResearch PersonnelResistanceResourcesRoleScreening procedureSerotypingSiteSmall Interfering RNAStem cellsStrokeTechnologyTestingTherapeuticTrainingUniversitiesWild Type MouseWritingapoptosis inducing factorbasecell typecellular engineeringdisabilityendonucleasehigh throughput screeninghistone methyltransferasehistone modificationhuman AMID proteinin vivoinnovationinsightloss of functionmedical schoolsmortalitymutantneuroprotectionneurotoxicitynovelnovel therapeuticsnucleaseprogramsskillsstem
项目摘要
DESCRIPTION (provided by applicant): Adult neurons are crucial and precious cell types controlling human body functions. Neuron injury following stroke and other neurologic diseases causes a significant loss of function. My long-term goal is to investigate the molecular mechanisms of neuronal injury and develop novel therapeutic strategies to treat patients suffering neurologic dysfunction. Poly(ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in glutamate neurotoxicity and cerebral infarction, which is a primary cause of subsequent morbidity and mortality following stroke. PARP-1 knockout mice are robustly resistant to stroke. Thus, it is critically important to understand the molecular mechanisms underlying PARP-1-dependent cell death (parthanatos) in stroke. Mitochondrial apoptosis-inducing factor (AIF) release and translocation to the nucleus causes chromatinolysis, which is the commitment point for parthanatos. However, little is known how AIF induces chromatinolysis and neuronal death after its nuclear translocation, since AIF itself has no endonuclease activity. Through an unbiased 17K human protein chip screening and a second siRNA-based PARP-1-dependent cell viability high-throughput screening, thirteen hits including AIF interactor 18 and protein arginine methyltransferase 6 (PRMT6) were identified. Here we focus on AIF interactor 18 as our preliminary data showed that knockdown of AIF interactor 18 is as protective as PARP-1 knockdown in parthanatos and it possesses hitherto unidentified endonuclease activity. Therefore, we name AIF interactor 18 as PAAN1 (Parthanatos-dependent AIF-Associated Nuclease 1). In the mentored K99 phase, we will first define the role of PAAN1 in ischemic neuronal death both in vitro and in vivo. We will then determine the specific PAAN1 endonuclease activity and determine if its endonuclease activity is required for neuronal injury. Histone post-translational modifications may regulate PAAN1 recognition in tightly wrapped genomic DNA to induce chromatinolysis and cell death after PARP-1 activation. PRMT6, a histone methyltransferase, was identified to be involved in parthanatos. In the independent R00 phase, I will study the role of PRMT6 in PAAN1-mediated ischemic cell death to understand the mechanism of PAAN1 recruitment to the DNA damage sites. I will further identify and characterize the functional PAAN1-interacting proteins required for parthanatos using two high-throughput screens, in order to understand how PAAN1 endonuclease activity is regulated by its networks. The successful completion of this project will yield important insights into cellular control of PAAN1 endonuclease activity and parthanatos and may provide new targets for developing innovative therapeutic approaches to treat patients with stroke. The mentored approach will be conducted in the laboratories of Drs. Valina and Ted Dawson and Dr. Raymond Koehler at the Johns Hopkins University School of Medicine. I have access to the resources available to Drs. Dawson and Koehler laboratories and the Neuroregeneration and Stem Cell Programs in Institute for Cell Engineering. To successfully accomplish the proposed research, during the mentored phase, I intend to take epigenetics courses and acquire skills in experimental stroke models and bioinformatics technologies, as well as grant writing and teaching skills. This training will allow me to expand my expertise and help my transition into a successful independent academic researcher.
PUBLIC HEALTH RELEVANCE: Stroke is the second cause of death and disability in the world. Parthanatos following stroke or other neurologic diseases is a primary cause for the subsequent death, disability and loss of quality of life. Understanding the mechanisms underlying parthanatos will offer innovative therapeutic approaches to treat patients with stroke or other neurologic diseases.
描述(申请人提供):成年神经元是控制人体功能的关键和宝贵的细胞类型。中风和其他神经系统疾病后的神经元损伤会导致严重的功能丧失。我的长期目标是研究神经元损伤的分子机制,并开发新的治疗策略来治疗神经功能障碍患者。多聚(ADP-核糖)聚合酶-1(PARP-1)在谷氨酸神经毒性和脑梗塞中起关键作用,而脑梗塞是卒中后继发发病率和死亡率的主要原因。PARP-1基因敲除小鼠对中风有很强的抵抗力。因此,了解卒中中依赖PARP-1的细胞死亡(副死亡症)的分子机制至关重要。线粒体凋亡诱导因子(AIF)的释放和移位导致核染色质溶解,这是肝细胞死亡的承诺点。然而,由于AIF本身没有核酸内切酶活性,因此AIF在其核转位后如何诱导染色质溶解和神经元死亡的机制还知之甚少。通过无偏的17K人蛋白芯片筛选和第二次基于siRNA的依赖PARP-1的细胞活性高通量筛选,鉴定了包括AIF相互作用蛋白18和蛋白精氨酸甲基转移酶6(PRMT6)在内的13个HIT。在这里,我们关注AIF相互作用元件18,因为我们的初步数据表明,AIF相互作用元件18的敲除在鹦鹉中具有与PARP-1敲除一样的保护作用,并且它具有迄今未知的内切酶活性。因此,我们将AIF相互作用因子18命名为PAAN1(Parathatos依赖的AIF相关核酸酶1)。在指导的K99阶段,我们将首先确定PAAN1在体外和体内缺血性神经元死亡中的作用。然后,我们将确定特定的PAAN1内切酶活性,并确定其内切酶活性是否是神经元损伤所必需的。组蛋白翻译后修饰可能调节紧密包裹的基因组DNA中PAAN1的识别,从而在PARP-1激活后诱导染色质溶解和细胞死亡。PRMT6是一种组蛋白甲基转移酶,被认为参与了甲胎蛋白的死亡。在独立的R00期,我将研究PRMT6在PAAN1介导的缺血细胞死亡中的作用,以了解PAAN1募集到DNA损伤部位的机制。我将使用两个高通量筛选进一步鉴定和鉴定甲胎蛋白所需的PAAN1相互作用蛋白的功能,以便了解PAAN1内切酶活性是如何受其网络调节的。该项目的成功完成将对PAAN1核酸内切酶活性和甲状旁腺激素的细胞控制产生重要的见解,并可能为开发治疗中风患者的创新治疗方法提供新的靶点。这种有指导的方法将在约翰·霍普金斯大学医学院的瓦利纳博士和泰德·道森博士以及雷蒙德·科勒博士的实验室进行。我可以使用Dawson博士和Koehler博士的实验室以及细胞工程研究所的神经再生和干细胞项目。为了成功地完成拟议的研究,在指导阶段,我打算参加表观遗传学课程,获得实验性中风模型和生物信息学技术方面的技能,以及赠款撰写和教学技能。这次培训将使我扩大我的专业知识,并帮助我转变为一名成功的独立学术研究人员。
公共卫生相关性:中风是世界上第二大致死和致残原因。中风或其他神经系统疾病后的死亡症是导致随后死亡、残疾和生活质量下降的主要原因。了解帕拉泰诺的潜在机制将为治疗中风或其他神经系统疾病的患者提供创新的治疗方法。
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(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Yingfei Wang其他文献
Yingfei Wang的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Yingfei Wang', 18)}}的其他基金
Role of KDM6B in Alzheimer’s disease related dementia
KDM6B 在阿尔茨海默病相关痴呆中的作用
- 批准号:
10739281 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
The role of AIF3 in neurodegeneration of Alzheimer's disease
AIF3在阿尔茨海默病神经退行性疾病中的作用
- 批准号:
10190767 - 财政年份:2019
- 资助金额:
$ 9.48万 - 项目类别:
The role of AIF3 in neurodegeneration of Alzheimer's disease
AIF3在阿尔茨海默病神经退行性疾病中的作用
- 批准号:
10626004 - 财政年份:2019
- 资助金额:
$ 9.48万 - 项目类别:
The role of AIF3 in neurodegeneration of Alzheimer's disease
AIF3在阿尔茨海默病神经退行性疾病中的作用
- 批准号:
10434704 - 财政年份:2019
- 资助金额:
$ 9.48万 - 项目类别:
The role of AIF3 in neurodegeneration of Alzheimer's disease
AIF3在阿尔茨海默病神经退行性疾病中的作用
- 批准号:
10017857 - 财政年份:2019
- 资助金额:
$ 9.48万 - 项目类别:
PARP-1 Signaling in DNA Damage and Cell Death
DNA 损伤和细胞死亡中的 PARP-1 信号转导
- 批准号:
10224826 - 财政年份:2017
- 资助金额:
$ 9.48万 - 项目类别:
PARP-1 Signaling in DNA Damage and Cell Death
DNA 损伤和细胞死亡中的 PARP-1 信号转导
- 批准号:
9753761 - 财政年份:2017
- 资助金额:
$ 9.48万 - 项目类别:
The role of a novel AIF-associated nuclease PAAN1 in neuronal injury
新型 AIF 相关核酸酶 PAAN1 在神经元损伤中的作用
- 批准号:
9197695 - 财政年份:2012
- 资助金额:
$ 9.48万 - 项目类别:
The role of a novel AIF-associated nuclease PAAN1 in neuronal injury
新型 AIF 相关核酸酶 PAAN1 在神经元损伤中的作用
- 批准号:
8986742 - 财政年份:2012
- 资助金额:
$ 9.48万 - 项目类别:
The role of a novel AIF-associated nuclease PAAN1 in neuronal injury
新型 AIF 相关核酸酶 PAAN1 在神经元损伤中的作用
- 批准号:
8545914 - 财政年份:2012
- 资助金额:
$ 9.48万 - 项目类别:
相似海外基金
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
- 批准号:
BB/Y006380/1 - 财政年份:2024
- 资助金额:
$ 9.48万 - 项目类别:
Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
- 批准号:
24K17112 - 财政年份:2024
- 资助金额:
$ 9.48万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
- 批准号:
23K04668 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
- 批准号:
23K06918 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
- 批准号:
23K05758 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Design and Synthesis of Fluorescent Amino Acids: Novel Tools for Biological Imaging
荧光氨基酸的设计与合成:生物成像的新工具
- 批准号:
2888395 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Studentship
Collaborative Research: RUI: Elucidating Design Rules for non-NRPS Incorporation of Amino Acids on Polyketide Scaffolds
合作研究:RUI:阐明聚酮化合物支架上非 NRPS 氨基酸掺入的设计规则
- 批准号:
2300890 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Continuing Grant
Structurally engineered N-acyl amino acids for the treatment of NASH
用于治疗 NASH 的结构工程 N-酰基氨基酸
- 批准号:
10761044 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Lifestyle, branched-chain amino acids, and cardiovascular risk factors: a randomized trial
生活方式、支链氨基酸和心血管危险因素:一项随机试验
- 批准号:
10728925 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别:
Single-molecule protein sequencing by barcoding of N-terminal amino acids
通过 N 端氨基酸条形码进行单分子蛋白质测序
- 批准号:
10757309 - 财政年份:2023
- 资助金额:
$ 9.48万 - 项目类别: