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: 10351838
• 负责人: RUBEN K DAGDA
• 金额: $ 5.06万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10351838
• 关键词: A kinase anchoring protein; Academia; Adaptor Signaling Protein; Address; Administrative Supplement; Adolescent; Award; Bioenergetics; Biological Assay; Biology; Brain; Brain-Derived Neurotrophic Factor; Cleaved cell; Complement; Cyclic AMP-Dependent Protein Kinases; Cytosol; Data; Dendrites; Development; Disadvantaged; Disease; Disease model; Doctor of Philosophy; Dynamin; Female; Foundations; Funding; Generations; Goals; Grant; Health; Homeostasis; Human; Imaging Techniques; Immunofluorescence Immunologic; Kinetins; Knowledge; Length; Maintenance; Mediating; Mentors; Midbrain structure; Mitochondria; Modeling; Molecular; Morphology; Movement; Mutate; Mutation; National Research Service Awards; Nerve Degeneration; Nerve Growth Factors; Neurons; Neurosciences; Neurotrophic Tyrosine Kinase Receptor Type 2; Oxidative Phosphorylation; Oxidative Stress; PTEN gene; Parents; Parkinson Disease; Peptide Hydrolases; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Presynaptic Terminals; Production; Protein Kinase; Protein Kinase A Inhibitor; Protein-Serine-Threonine Kinases; Proteins; Recombinants; Regulation; Research; Research Activity; Research Personnel; Research Project Grants; Research Support; Resistance; Respiration; Scaffolding Protein; Signal Transduction; Site; Soman; Specificity; Substantia nigra structure; Synaptic plasticity; Talents; Technical Expertise; Techniques; Testing; Time; Training; United States National Institutes of Health; Work; base; career development; cinematography; disadvantaged background; doctoral student; dopaminergic neuron; expectation; extracellular; graduate student; innovation; mitochondrial dysfunction; mutant; neuronal survival; neuroprotection; parent grant; post-doctoral training; postsynaptic; pre-doctoral; protein kinase inhibitor; skills; time use; tool development; trafficking; tripolyphosphate

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诱导的丝氨酸苏氨酸激酶1(PINK1)的突变 定位于线粒体和胞浆室，与家族性帕金森氏症有关 疾病(PD)。PINK1激活下游蛋白激酶A(PKA)调节线粒体 树枝状晶体中的贩运、含量和融合。通过资助机构的支持获得的初步数据 家长资助表明，大脑中PINK1激活的生理后果之一是 产生脑源性神经营养因子(BDNF)来调节突触的可塑性和生存。 虽然已知BDNFs调节神经元的生存、发育和可塑性，但新的证据表明， 来自我们研究组的研究表明，BDNF可以调节生物能量学和树突的生长 通过加强突触后线粒体的氧化磷酸化、运输和融合。 目标：这项为期两年的行政补充补助金的首要目标是支持 第一代女性神经科学的研究活动和临界保护研究时间 博士生(斯温女士)出身不利。Swain女士获得的初步数据 目前研究表明，内源性裂解PINK1(c-PINK1)的药理激活增强了 脑源性神经营养因子的产生，以及外源性重组人脑源性神经营养因子对神经元的影响 线粒体在树突中的移动和增加在树突中的线粒体融合。通过提供 她介绍了职业发展工具、神经退行性变的基本概念和技术技能。 Maryann Swain将检验这一假设，即神经元暴露于细胞外BDNF可促进 线粒体向神经元(树突和突触)高能量需求部位的运动 终端)，增加线粒体的互联(融合)，并促进能量的产生 通过PKA介导的线粒体关键底物的磷酸化。建议数 Swain女士开展的补充活动是相辅相成的，在家长的范围内 与第二个目标相关的授予(cPINK1如何调控线粒体交易 树突)目的3(c-PINK1如何通过调节树突生长)。具体目标1：cPINK1和cPINK1如何 BDNF通过PINK1和PKA调节树突内线粒体的运输/含量。特定的 目的2：确定cPINK1和BDNF如何通过促进树突线粒体融合 PINK1和PKA。影响：Maryann Swain女士将在2- 年度行政副刊不仅将增强技术和概念技能，使她 在第一年补充课程结束前提交一份有竞争力的NRSA博士前提案 支持，但会让她取得成功，实现她成为独立人士的目标 学术界神经退行性变研究员。