Determining Mechanisms of DLK Regulation in Axon Injury Responses
确定轴突损伤反应中 DLK 调节的机制
基本信息
- 批准号:9302559
- 负责人:
- 金额:$ 6.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAfferent NeuronsAlzheimer&aposs DiseaseAutomobile DrivingAxonBindingBiochemicalBiologyCRISPR/Cas technologyCell DeathCell LineCellsCessation of lifeClinicalDataDiseaseFamilyGenesGeneticGenetic ScreeningGenome engineeringGlaucomaGoalsHindlimbImage AnalysisInjuryIschemic Brain InjuryKnockout MiceKnowledgeLeucine ZippersMAPK8 geneMaintenanceMediatingMitogen-Activated Protein KinasesModelingMolecularMultiple SclerosisMultiple TraumaMusMuscleNatural regenerationNervous System TraumaNervous system structureNeurodegenerative DisordersNeuronal InjuryNeuronsNumbnessOutcomeParalysedParkinson DiseasePathway interactionsPeripheralPeripheral Nervous System DiseasesPeripheral nerve injuryPharmacologyPhenotypePhosphotransferasesPlayProtein InhibitionProteinsRegulationRoleSignal PathwaySignal TransductionSpinal cord injuryTechniquesTestingTherapeutic InterventionTranscriptional ActivationUniversitiesWashingtonaxon injuryaxon regenerationaxonal degenerationbasedisabilityeffective therapyexperimental studygain of functionimmunocytochemistryin vivoinduced pluripotent stem cellinhibitor/antagonistinjuredknockout animalmolecular markermolecular targeted therapiesnerve supplynervous system disorderneuron lossnew therapeutic targetnoveloverexpressionpainful neuropathyprogramsprotein functionpublic health relevanceregenerativerepairedresponseresponse to injurysciatic nervesensorsuccesstherapeutic evaluationtherapeutic targettranscription factortranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Neuronal cell death and axonal damage are hallmarks of many neurological disorders and neurodegenerative diseases including, Alzheimer's and Parkinson's diseases, spinal cord injury, glaucoma, multiple sclerosis, traumatic and ischemic brain injuries, and over 100 different peripheral neuropathies. The dual leucine zipper kinase (DLK, MAP3K12) is a key sensor of axon injury and contributes to three distinct neuronal outcomes: (1) cell death, (2) axon degeneration (AxD), and (3) axon regeneration (AxR). Thus DLK signaling is an exciting new therapeutic target for a wide range of neurological disorders and injury. In spite of the clinical importance for targeting DLK signaling, we know shockingly little about how DLK is regulated and contributes to neuronal outcome after injury. This proposal will address this fundamental gap in our knowledge and will identify regulators of DLK and test their roles in neuronal injury signaling and outcomes. I performed a pilot screen to identify proteins that restrict DLK signaling in DRG neurons, and identified MAP3K12 binding inhibitor protein (MBIP) as a negative regulator of DLK. In Aim 1, I will determine the mechanism by which MBIP regulates DLK signaling. This will involve genetic and pharmacological manipulation of DLK signaling and assessment of each level of the pathway. In Aim 1, I will also test the hypothesis that injury relieves MBIP-inhibition of DLK and manipulating MBIP is sufficient to alter the injury phenotype in models of DLK-dependent cell death, AxD, and AxR. In Aim 2, I will test the hypothesis that MBIP regulates basal DLK-signaling in vivo by assessing spontaneous DLK pathway activation. Furthermore, I will test the role of MBIP in peripheral nerve injury. This will be accomplished using multiple readouts of AxD and AxR in the sciatic nerve and re-innervation of hindlimb muscles. Aims 1 and 2 will (1) elucidate the mechanism by which MBIP regulates DLK signaling and how this is affected by injury, (2) test the therapeutic potential of targeting MBIP after injury, and (3) determine the role of MBIP-mediated inhibition of
DLK signaling in vivo. Due to the success of my pilot screen, I propose a larger candidate-based screen to identify additional positive and negative regulators of DLK in Aim 3. Candidates will be evaluated for their ability to suppress or enhance molecular markers of the DLK signaling pathway. Hits will be further evaluated by testing their contributions to neuronal outcome in multiple injury models. This aim will identify novel regulators of the DLK pathway in mammalian sensory neurons and will lead to testable hypotheses to uncover mechanisms of DLK regulation and the impact on injury phenotypes. These aims will fill a critical gap in knowledge regarding mechanisms of DLK regulation and the relationship between DLK regulators and neuronal injury phenotypes. These results will significantly enhance our understanding of DLK signaling and may identify novel molecular targets for therapeutic intervention in a wide range of neuronal injuries and diseases.
描述(由申请人提供):神经元细胞死亡和轴突损伤是许多神经系统疾病和神经退行性疾病的标志,包括阿尔茨海默病和帕金森病、脊髓损伤、青光眼、多发性硬化、创伤性和缺血性脑损伤以及超过100种不同的周围神经病。双亮氨酸拉链激酶(DLK,MAP3K12)是轴突损伤的关键传感器,并且有助于三种不同的神经元结果:(1)细胞死亡,(2)轴突变性(AxD),和(3)轴突再生(AxR)。因此,DLK信号传导是一个令人兴奋的新的治疗目标,为广泛的神经系统疾病和损伤。尽管靶向DLK信号传导的临床重要性,但我们对DLK如何调节以及如何促进损伤后的神经元结果知之甚少。该提案将解决我们知识中的这一根本性差距,并将确定DLK的调节因子,并测试它们在神经元损伤信号传导和结果中的作用。我进行了初步筛选,以确定限制DRG神经元中DLK信号传导的蛋白质,并确定MAP3K12结合抑制蛋白(MBIP)为DLK的负调节因子。在目标1中,我将确定MBIP调节DLK信号传导的机制。这将涉及DLK信号传导的遗传和药理学操纵以及对途径的每个水平的评估。在目标1中,我还将检验以下假设:损伤缓解DLK的MBIP抑制,并且操纵MBIP足以改变DLK依赖性细胞死亡、AxD和AxR模型中的损伤表型。在目标2中,我将通过评估自发DLK通路激活来检验MBIP调节体内基础DLK信号传导的假设。此外,我将测试MBIP在周围神经损伤中的作用。这将使用坐骨神经中AxD和AxR的多次读数和后肢肌肉的神经支配来完成。目的1和2将(1)阐明MBIP调节DLK信号传导的机制以及损伤如何影响这一机制,(2)测试损伤后靶向MBIP的治疗潜力,以及(3)确定MBIP介导的DLK信号传导抑制的作用。
体内DLK信号传导。由于我的试点屏幕的成功,我建议一个更大的候选人为基础的屏幕,以确定其他积极和消极的DLK调节目标3。将评价候选物抑制或增强DLK信号传导途径的分子标志物的能力。将通过在多种损伤模型中测试其对神经元结果的贡献来进一步评价命中。这一目标将确定哺乳动物感觉神经元中DLK通路的新调节剂,并将导致可验证的假设,以揭示DLK调节机制和对损伤表型的影响。这些目标将填补一个关键的知识空白DLK调节机制和DLK调节剂和神经元损伤表型之间的关系。这些结果将显著增强我们对DLK信号传导的理解,并可能为广泛的神经元损伤和疾病的治疗干预确定新的分子靶点。
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 }}
Erin Frey其他文献
Erin Frey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('Erin Frey', 18)}}的其他基金
Determining Mechanisms of DLK Regulation in Axon Injury Responses
确定轴突损伤反应中 DLK 调节的机制
- 批准号:
9105188 - 财政年份:2015
- 资助金额:
$ 6.1万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 6.1万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 6.1万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 6.1万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 6.1万 - 项目类别:
Grant-in-Aid for Early-Career Scientists