Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease
帕金森病模型中 PINK1 和 PKA 对树突稳态的调节
基本信息
- 批准号:10351838
- 负责人:
- 金额:$ 5.06万
- 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:2021-04-15 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAcademiaAdaptor Signaling ProteinAddressAdministrative SupplementAdolescentAwardBioenergeticsBiological AssayBiologyBrainBrain-Derived Neurotrophic FactorCleaved cellComplementCyclic AMP-Dependent Protein KinasesCytosolDataDendritesDevelopmentDisadvantagedDiseaseDisease modelDoctor of PhilosophyDynaminFemaleFoundationsFundingGenerationsGoalsGrantHealthHomeostasisHumanImaging TechniquesImmunofluorescence ImmunologicKinetinsKnowledgeLengthMaintenanceMediatingMentorsMidbrain structureMitochondriaModelingMolecularMorphologyMovementMutateMutationNational Research Service AwardsNerve DegenerationNerve Growth FactorsNeuronsNeurosciencesNeurotrophic Tyrosine Kinase Receptor Type 2Oxidative PhosphorylationOxidative StressPTEN geneParentsParkinson DiseasePeptide HydrolasesPharmacologyPhosphorylationPhosphotransferasesPhysiologicalPresynaptic TerminalsProductionProtein KinaseProtein Kinase A InhibitorProtein-Serine-Threonine KinasesProteinsRecombinantsRegulationResearchResearch ActivityResearch PersonnelResearch Project GrantsResearch SupportResistanceRespirationScaffolding ProteinSignal TransductionSiteSomanSpecificitySubstantia nigra structureSynaptic plasticityTalentsTechnical ExpertiseTechniquesTestingTimeTrainingUnited States National Institutes of HealthWorkbasecareer developmentcinematographydisadvantaged backgrounddoctoral studentdopaminergic neuronexpectationextracellulargraduate studentinnovationmitochondrial dysfunctionmutantneuronal survivalneuroprotectionparent grantpost-doctoral trainingpostsynapticpre-doctoralprotein kinase inhibitorskillstime usetool developmenttraffickingtripolyphosphate
项目摘要
Background/Premise: Mutations in PTEN-induced Kinase 1 (PINK1), a serine threonine kinase
localized to mitochondrial and cytosolic compartments, is associated with familial forms of Parkinon’s
Disease (PD). PINK1 activates downstream Protein Kinase A (PKA) to regulate mitochondrial
trafficking, content and fusion in dendrites. Preliminary data garnered via the support of the funded
parent grant suggest that one of the physiological consequences of PINK1 activation in the brain is the
production of brain-derived neurotrophic factor (BDNF) to modulate synaptic plasticity and survival.
While it is known that BDNFs regulate neuronal survival, development and plasticity, emerging evidence
from our research group suggests that BDNF can modulate the bioenergetics and dendrite outgrowth of
neurons by enhancing oxidative phosphorylation, trafficking and fusion of postsynaptic mitochondria.
Objective: For this two-year administrative supplement grant, the overarching goal is to support the
research activities and critical protected research time of a first-year generation, female Neuroscience
Ph.D. student (Ms. Swain) from a disadvantage background. Preliminary data garnered by Ms. Swain
currently show that pharmacological activation of endogenous cleaved PINK1 (c-PINK1) enhances the
production of BDNF, and that exposing neurons to exogenous recombinant human BDNF increases
mitochondrial movement in dendrites and increases mitochondrial fusion in dendrites. By providing
her the career development tools, foundational concepts in neurodegeneration and technical skills, Ms.
Maryann Swain will test the hypothesis that the exposure of neurons to extracellular BDNF promotes
the movement of mitochondria to sites of high energy demand in neurons (dendrites and synaptic
terminals), increases mitochondrial interconnectivity (fusion), and boosts energy production in the
brain via PKA-mediated phosphorylation of key substrates in mitochondria. The proposed
supplemental activities performed by Ms. Swain are complementary and within the scope of the parent
grant as they relate to the second aim (how cPINK1 regulates mitochondrial trafficking in
dendrites)aim 3 (how c-PINK1 regulates dendrite outgrowth via ). Specific Aim 1: how cPINK1 and
BDNF regulates mitochondrial trafficking/content in dendrites through PINK1 and PKA. Specific
Aim 2: Determine how cPINK1 and BDNF increases mitochondrial fusion in dendrites through
PINK1 and PKA. Impact: The training that Ms. Maryann Swain will receive under the support of a 2-
year administrative supplement will not only enhance the technical and conceptual skills to enable her
to submit a competitive NRSA predoctoral proposal by the end of the first year of supplemental
support, but will allow her to be successful and attain her goal of becoming an independent
neurodegeneration researcher in academia.
背景/前提:PTEN诱导的激酶1(pink1)中的突变,丝氨酸苏氨酸激酶
位于线粒体和胞质室的本地化与帕克宁家庭形式有关
疾病(PD)。 Pink1激活下游蛋白激酶A(PKA)来调节线粒体
树突中的贩运,内容和融合。通过资助的支持获得的初步数据
父母的赠款表明,大脑中Pink1激活的物理后果之一是
产生脑衍生的神经营养因子(BDNF)以调节突触可塑性和存活率。
虽然众所周知,BDNF调节神经元的生存,发育和可塑性,但新出现的证据
我们的研究小组提出,BDNF可以调节生物能和树突生物的生长
通过增强突触后线粒体的氧化磷酸化,运输和融合的神经元。
目的:对于这两年的行政补充赠款,总体目标是支持
第一代女性神经科学的研究活动和受保护的研究时间
博士来自灾难背景的学生(Swain女士)。 Swain女士获得的初步数据
目前表明,内源性裂解的Pink1(C-Pink1)的药物激活增强了
BDNF的产生,以及将神经元暴露于外源重组人BDNF增加
树突中的线粒体运动,并增加树突中的线粒体融合。通过提供
她的职业发展工具,神经退行性和技术技能的基础概念,女士。
Maryann Swain将检验以下假设:神经元暴露于细胞外BDNF会促进
线粒体向神经元(树突和突触的高能量需求的位点)的运动
终端),增加线粒体互连(融合),并提高了能源的产生
通过PKA介导的线粒体中关键底物的磷酸化大脑。提议
Swain女士进行的补充活动已完成,并且在父母的范围内
与第二个目标有关的授予(CPINK1如何调节线粒体贩运
dendrites)AIM 3(C-Pink1如何调节树突生长的via)。特定目标1:cpink1和
BDNF通过PINK1和PKA调节树突中的线粒体贩运/含量。具体的
AIM 2:确定CPINK1和BDNF如何通过树突中的线粒体融合增加
Pink1和PKA。影响:Maryann Swain女士将在2-的支持下接受的培训
一年的行政补充不仅会增强技术和概念技能,使她能够
在补充第一年结束之前提交有竞争力的NRSA
支持,但将使她取得成功并实现成为独立的目标
学术界的神经变性研究员。
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)
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{{ truncateString('RUBEN K DAGDA', 18)}}的其他基金
CBESS: a pipeline program to increase linguistic and geographic diversity in STEM + health
CBESS:一项旨在增加 STEM 健康领域语言和地理多样性的管道计划
- 批准号:
10665432 - 财政年份:2023
- 资助金额:
$ 5.06万 - 项目类别:
Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease
帕金森病模型中 PINK1 和 PKA 对树突稳态的调节
- 批准号:
9891110 - 财政年份:2018
- 资助金额:
$ 5.06万 - 项目类别:
Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease
帕金森病模型中 PINK1 和 PKA 对树突稳态的调节
- 批准号:
10263704 - 财政年份:2018
- 资助金额:
$ 5.06万 - 项目类别:
Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease
帕金森病模型中 PINK1 和 PKA 对树突稳态的调节
- 批准号:
10372026 - 财政年份:2018
- 资助金额:
$ 5.06万 - 项目类别:
Regulation of Dendrite Homeostasis by PINK1 and PKA in Models of Parkinson's Disease
帕金森病模型中 PINK1 和 PKA 对树突稳态的调节
- 批准号:
10531176 - 财政年份:2018
- 资助金额:
$ 5.06万 - 项目类别:
Community of Bilingual English-Spanish Speakers Exploring Issues in Science and Health (CBESS)
探索科学与健康问题的英语-西班牙语双语社区 (CBESS)
- 批准号:
9303182 - 财政年份:2017
- 资助金额:
$ 5.06万 - 项目类别:
Community of Bilingual English-Spanish Speakers Exploring Issues in Science and Health (CBESS)
探索科学与健康问题的英语-西班牙语双语社区 (CBESS)
- 批准号:
10017689 - 财政年份:2017
- 资助金额:
$ 5.06万 - 项目类别:
Community of Bilingual English-Spanish Speakers Exploring Issues in Science and Health (CBESS)
探索科学与健康问题的英语-西班牙语双语社区 (CBESS)
- 批准号:
10240614 - 财政年份:2017
- 资助金额:
$ 5.06万 - 项目类别:
Community of Bilingual English-Spanish Speakers Exploring Issues in Science and Health (CBESS)
探索科学与健康问题的英语-西班牙语双语社区 (CBESS)
- 批准号:
9756429 - 财政年份:2017
- 资助金额:
$ 5.06万 - 项目类别:
Role of phospholipids in regulating neurotoxin induced mitochondrial autophagy
磷脂在调节神经毒素诱导的线粒体自噬中的作用
- 批准号:
7333576 - 财政年份:2007
- 资助金额:
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