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: 9349907
• 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/9349907
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyotrophic Lateral Sclerosis; Attenuated; Axonal Transport; Behavior; Behavioral; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Caveolins; Cell membrane; Cells; Chemicals; Cholesterol; Chronic; Cognitive; Communication; Comorbidity; Complementary DNA; Cues; Cyclic AMP; Dendritic Spines; Dopamine; Dopamine Receptor; Electrophysiology (science); Event; Exercise; Exercise Therapy; Fright; Genes; 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; Neurodegenerative Disorders; 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; 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; experimental study; extracellular; functional plasticity; gene therapy; 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约 8700 万。[年龄本身就是最大的风险因素 发展为阿尔茨海默病（AD）和其他形式的神经退行性疾病，例如帕金森病（PD）， 肌萎缩侧索硬化症 (ALS) 或抑郁症。] 如果没有预防或治疗，与年龄相关的 到 2050 年，神经退行性疾病患者可能会达到 11-1600 万人。到 2035 年，今天的退伍军人将步入中年， 像老年越南退伍军人那样的健康问题，由于创伤后应激障碍而变得更加复杂 障碍、创伤性脑损伤和多发伤。在神经退行性变期间，大脑表现出区域- 神经元形态的特定改变、结构可塑性和树突分支的减少以及 再生能力下降。大脑功能由电活动和化学活动支撑 神经元之间的通讯；细胞之间的这种通讯对于重建正常状态是必要的 AD 大脑中的大脑功能。除了启动神经元生长的基因调节之外，其他 干预措施，例如 1) 选择性血清素和多巴胺再摄取抑制 (SDRI) 以促进 cAMP，或 2) [神经营养蛋白受体激动剂]可以促进结构和功能可塑性并改善行为 患有AD的人。适当的神经元生长和指导取决于来自 通过质膜的细胞外信号（即空间信息）。一个关键的质膜“枢纽” 将细胞外信号转导至潜在的细胞骨架机制是膜/脂筏（MLR）， 富含鞘脂、胆固醇和支架蛋白 Caveolin-1 (Cav-1) 的离散微结构域。 神经元极化和运动取决于位于其前缘的 MLR。我们之前有过 证明了神经元靶向的 Cav-1 过度表达（通过将其与神经元特异性连接来实现） 突触蛋白启动子 [SynCav1])：1) 增强膜胆固醇、MLR 形成和突触受体 表达和信号转导 (TrkB)； 2）增加血清素受体（5-HT6）和多巴胺受体介导的 (D1R) cAMP 形成； 3）即使在生长的情况下也能促进树突发芽和分枝 抑制剂。我们小组最近发表的一篇开创性出版物表明，将 SynCav1 直接递送到 大脑增强成年小鼠（6个月）和老年小鼠（20岁）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依赖性情境恐惧学习和记忆。 这些结果提供了概念验证证据，表明通过增加神经元中 Cav-1 的表达， 人们可以通过积极的行为结果来改善结构和功能的神经可塑性。这个应用程序 试图确定 SynCav1 是否可以在分化的人类中诱导类似的神经塑性变化 源自诱导多能干细胞 (iPSC) 的神经元干细胞 (NSC)，然后使用 SynCav1 与 SSRIs、SDRIs 或 TrkB 激动剂联合使用可显着提高行为改善率 在 AD 小鼠中。我们的研究将利用成人分化神经元干细胞的新型体外模型 （NSC）衍生形式诱导多能干细胞（iPSC）与量子点轴突运输时间相结合- 用于评估神经元功能以及体内遗传干预、药理学和运动的延时成像 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。完成所提出的实验可以证明使用新颖的方法是合理的 针对 Cav-1 和 MLR 的治疗干预措施（小分子、肽、基因操作） 旨在对抗退伍军人群体中与 AD 相关的神经变性或神经损伤。