Caveolin-mediated neuronal signaling in differentiated adult human neuronal stem cells and the aging brain

分化的成人神经元干细胞和衰老大脑中小窝蛋白介导的神经元信号传导

• 批准号: 9898275
• 负责人: BRIAN P HEAD
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898275
• 关键词: Adult; Age; Aging; Agonist; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Amyotrophic Lateral Sclerosis; Attenuated; Axonal Transport; Behavior; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Caveolins; Cell membrane; Cells; Chemicals; Cholesterol; Chronic; Cognitive; Communication; Complementary DNA; Cues; Cyclic AMP; Dendritic Spines; Dopamine; Dopamine Receptor; Electrophysiology (science); Event; Exercise; Exercise Therapy; Financial Hardship; Fright; Genetic; Growth; Growth Cones; Growth Inhibitors; Health; Health Care Costs; Healthcare Systems; Hippocampus (Brain); Human; Image; In Vitro; Individual; Intervention; Lead; Learning; Link; Maintenance; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Memory; Mental Depression; Molecular Target; Morbidity - disease rate; Morphology; Motor; Mus; Natural regeneration; Nerve; Nerve Degeneration; Nerve Growth Factor Receptors; Neuronal Differentiation; Neuronal Plasticity; Neurons; Parkinson Disease; Peptides; Pharmacology; Population; Post-Traumatic Stress Disorders; Prevention; Publications; Publishing; Quantum Dots; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Risk Factors; Scaffolding Protein; Scanning Electron Microscopy; Seminal; Serotonin; Signal Transduction; Sphingolipids; Structure; Synapses; Synapsins; Synaptic Receptors; Techniques; Testing; Therapeutic; Time; Trauma; Traumatic Brain Injury; Veterans; Vietnam; Work; age related; age related neurodegeneration; aged; aging brain; axon growth; behavioral outcome; caveolin 1; cell motility; clinically relevant; cognitive function; combat; comorbidity; experimental study; extracellular; functional plasticity; gene therapy; genetic manipulation; improved; in vitro Model; in vivo; induced pluripotent stem cell; middle age; mouse model; multimodality; nerve injury; nerve stem cell; neurite growth; neuronal growth; neuronal guidance; neurotransmission; novel; novel strategies; novel therapeutic intervention; overexpression; promoter; receptor; receptor expression; reuptake; serotonin receptor; small molecule; social; synaptogenesis

The population over 65 will increase to ~87 million by 2050. [Age alone is the greatest risk factor for developing Alzheimer's disease (AD) and other forms of neurodegeneration such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) or depression.] With no prevention or treatment, aged-related neurodegeneration could reach 11-16 million by 2050. In 2035, today's Veterans will be middle-aged, with health issues like those seen in aging Vietnam Veterans, complicated by comorbidities of posttraumatic stress disorder, traumatic brain injury, and polytrauma. During neurodegeneration, the brain demonstrates region- specific alterations in neuronal morphology, reduced structural plasticity and dendritic branching, and a decreased capacity to regenerate. Brain function is underpinned by both electrical activity and chemical communication between neurons; this communication between cells is necessary for re-establishing normal brain function in the AD brain. In addition to genetic modulation that initiate neuronal growth, other interventions such as 1) selective serotonin and dopamine reuptake inhibition (SDRI) to promote cAMP, or 2) [neurotrophin receptor agonism] may promote structural and functional plasticity and improve behavior in individuals afflicted with AD. Proper neuronal growth and guidance is dependent upon communication from extracellular signals (i.e., spatial information) through the plasma membrane. A key plasmalemmal `hub' that transduces the extracellular cues to the underlying cytoskeletal machinery are membrane/lipid rafts (MLR), discrete microdomains enriched in sphingolipids, cholesterol, and scaffolding protein caveolin-1 (Cav-1). Neuronal polarization and motility is dependent upon MLR localized in its leading edge. We have previously demonstrated that neuron-targeted Cav-1 over-expression (achieved by linking it to a neuron-specific synapsin promoter [SynCav1]): 1) enhances membrane cholesterol, MLR formation, and synaptic receptor expression and signaling (TrkB); 2) increases serotonin receptor (5-HT6) and dopamine receptor-mediated (D1R) cAMP formation; 3) promotes dendritic sprouting and arborization even in the presence of growth inhibitors. A recent seminal publication from our group demonstrates that direct delivery of SynCav1 into the brain augments structural and functional hippocampal neuroplasticity in adult mice (6 mo) and aged mice (20 mo) and improves hippocampal-dependent contextual fear learning and memory in both adult and aged mice. These results provide proof-of-concept evidence that by increasing expression of Cav-1 specifically in neurons, one can improve structural and functional neuroplasticity with positive behavioral outcome. This application seeks to determine whether SynCav1 can induce similar neuroplastic changes in differentiated human neuronal stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) and then to use SynCav1 in combination with SSRIs, SDRIs, or TrkB agonism to significantly augment the rate of behavioral improvement in AD mice. Our study will utilize a novel in vitro model of adult human differentiated neuronal stem cells (NSCs) derived form induced pluripotent stem cells (iPSCs) combined with quantum dot axonal transport time- lapse imaging to assess neuronal function, and in vivo genetic interventions, pharmacological, and exercise therapeutic techniques, electrophysiology, confocal and scanning electron microscopy, and motor and cognitive batteries. Completion of the proposed experiments could lead to the justification of using novel therapeutic interventions (small molecules, peptides, gene manipulation) that target Cav-1 and MLR for the purpose of combating AD-associated neurodegeneration or nerve trauma in the Veteran population.

到2050年，65岁以上的人口将增加到8700万。年龄本身就是患糖尿病的最大风险因素 发展为阿尔茨海默病(AD)和其他形式的神经退化，如帕金森氏病(PD)， 肌萎缩侧索硬化症(ALS)或抑郁症。]没有预防或治疗，与老年人有关 到2050年，神经退行性变可能达到1100-1600万。到2035年，今天的退伍军人将是中年人， 像越南老兵那样的健康问题，并伴有创伤后应激障碍 精神障碍、创伤性脑损伤和多发性创伤。在神经退行性变过程中，大脑显示出- 神经元形态的特殊改变，结构可塑性降低和树突分支，以及 再生能力降低。大脑功能是由电活动和化学物质共同支撑的 神经元之间的通信；细胞之间的通信对于重建正常是必要的 阿尔茨海默病患者的大脑功能。除了启动神经元生长的基因调控外，其他 干预措施，如1)选择性5-羟色胺和多巴胺再摄取抑制(SDRI)以促进cAMP，或2) [神经营养素受体激动剂]可能促进结构和功能的可塑性并改善行为 患有阿尔茨海默病的个人。适当的神经元生长和引导依赖于来自 通过质膜传递细胞外信号(即空间信息)。一个关键的质膜‘中枢’ 转导细胞外信号到潜在的细胞骨架机制是膜/脂筏(MLR)， 分离的微域富含鞘脂、胆固醇和支架蛋白Cav-1(Cav-1)。 神经元的极化和运动依赖于位于其前缘的MLR。我们之前已经 证明了神经元靶向Cav-1的过度表达(通过将其与神经元特异性的 突触素启动子[SynCav1])：1)促进膜胆固醇、MLR的形成和突触受体 表达和信号转导(TrkB)；2)增加5-HT6受体和多巴胺受体介导 (D1R)cAMP的形成；3)即使在生长的情况下也促进树枝萌发和树枝形成 抑制剂。我们团队最近发表的一篇开创性文章表明，直接将SynCav1导入到 大脑增强成年小鼠(6个月)和老年小鼠(20个月)的结构和功能海马神经可塑性 Mo)，并改善成年和老年小鼠的海马区依赖的情景恐惧学习和记忆。 这些结果提供了概念验证证据，证明通过增加Cav-1在神经元中的特异性表达， 一种可以改善结构和功能的神经可塑性，并具有积极的行为结果。此应用程序 旨在确定SynCav1是否可以在分化的人类中诱导类似的神经可塑性变化 诱导多能干细胞(IPSCs)来源的神经干细胞(NSCs)及其与SynCav1的联合应用 与SSRIs、SDRI或TrkB激动剂联合使用可显著提高行为改善率 在AD小鼠中。我们的研究将利用一种新的成人分化神经干细胞的体外模型 (NSCs)来源于诱导多能干细胞(IPSCs)结合量子点轴突运输时间- 用于评估神经功能、体内遗传干预、药理学和运动的缺失成像 治疗技术，电生理学，共聚焦和扫描电子显微镜，以及运动和 认知电池。拟议的实验的完成可能会导致使用小说的合理性 针对Cav-1和MLR的治疗干预(小分子、多肽、基因操作) 目的是对抗退伍军人中与AD相关的神经退行性变或神经损伤。