Astrocyte Norrin, Norrie disease and Neurodegeneration

星形胶质细胞诺里蛋白、诺里病和神经变性

• 批准号: 10383676
• 负责人: Jeffrey D Rothstein
• 金额: $ 44.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383676
• 关键词: Adult; Affect; Age; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Astrocytes; Biology; Blood - brain barrier anatomy; Brain; Brain Diseases; Buffers; Cells; Childhood; Cognitive; Collaborations; Data; Defect; Dementia; Dendrites; Dendritic Spines; Development; Disease; Disease model; Frontotemporal Dementia; Functional disorder; Grant; Health; Heterogeneity; Homeostasis; Human; Immune signaling; In Vitro; Injury; Ions; Knockout Mice; Label; Length; Maintenance; Mental Retardation; Modeling; Molecular; Morphology; Motor Neuron Disease; Mutant Strains Mice; Mutate; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Neurotoxins; Neurotransmitters; Norrie' s disease; Pathogenesis; Pathway interactions; Play; Population; Process; Protein Analysis; Proteins; Protoplasm; RNA analysis; Rare Diseases; Regulation; Retinal Degeneration; Role; Spinal; Structure; Synapses; Testing; Therapeutic; Tissues; Transgenic Mice; Vertebral column; base; brain tissue; cell type; cerebral atrophy; chronic neurologic disease; density; extracellular; gray matter; in vivo; molecular marker; mouse model; mutant; nerve injury; nervous system disorder; neurotransmitter metabolism; novel; novel strategies; prevent; protein function; repaired; restoration; white matter

PROJECT SUMMARY Astroglia are essential for the homeostasis and maintenance of the central nervous system (CNS). They display a vast array of roles such as neurotransmitter metabolism, regulation of synaptic neurotransmitter clearance, extracellular ion buffering, neurotrophic release, immune signaling and blood-brain-barrier maintenance. It is not surprising that astroglia in different regions display diverse functions to maintain their environmental niche. Historically, astroglia were placed into two groups based on their neuroanatomical localization and morphological depictions: protoplasmic astroglia of the grey matter and fibrous astroglia of the white matter. Recent evidence has suggested that astroglia consist of different subpopulations, similar to neuronal functional and molecular heterogeneity. Nevertheless, there still remain large gaps in our understanding of these different subtypes due to a lack of molecular markers to identify and study these populations and how these different astrocytes serve to regulate neurons and their synapses. We recently generated a novel transgenic mouse model that selectively and robustly labels a specific astroglia subpopulation in the adult CNS and thru RNA and protein analyses, have learned that these astroglia are highly and selectively enriched in a secreted protein, norrin. A mutated form of norrin is the cause of a rare neurological degenerative disease, Norrie disease. Our preliminary studies strongly suggest that astroglial norrin plays a significant role in the local formation and/or maintenance of local dendrites and spines. We have early data to suggest that this astrocytic norrin regulates neuronal spine density and dendritic branching in cortical layers. Furthermore, our studies suggest that this astrocyte subpopulation is dramatically affected in amyotrophic lateral sclerosis. In collaboration with Jackson Labs, we recently generated a Norrie disease transgenic mouse which can allow us to explore this protein function in vivo and in disease. We plan several approaches to understand the biology of astroglial norrin and how it may alter dendrites/spines as well its contribution to neurodegeneration in ALS and Norrie disease. We propose to: 1) Evaluate the role of cortical astroglial Norrin in regulating neuronal dendrites and spines in vitro and in vivo. These studies will demonstrate the role that Norrin has in regulating neurons, primarily through dendritic and synaptic development and/or maintenance. 2) Determine whether astroglial mutant Norrin is sufficient to alter synaptic development and/or maintenance in vivo. We have first model of Norrie disease, and will test the hypothesis that norrin can rescue this neurodegenerative disease of astroglia. And 3) Investigate the loss of astroglial norrin in contributing to synaptic loss and neurodegeneration in motor neuron disease models and human ALS. These studies will evaluate the contribution of norrin to synaptic injury in several ALS models and human ALS. Taken together, these findings set the stage to study of this newly identified astrocyte subpopulation in both health and disease, including the potential to generate cell astrocyte-specific therapeutics for several neurological disorders.

项目摘要 星形胶质细胞对于中枢神经系统（CNS）的稳态和维持是必不可少的。他们 在神经递质代谢、调节突触神经递质等方面发挥着重要作用 清除、细胞外离子缓冲、神经营养素释放、免疫信号传导和血脑屏障 上维护不同区域的星形胶质细胞显示不同的功能来维持其功能，这并不奇怪。 环境生态位从历史上看，星形胶质细胞被分为两组基于其神经解剖学 定位和形态学观察：灰质的原生质星形胶质细胞和 白色物质。最近的证据表明，星形胶质细胞由不同的亚群组成，类似于 神经元功能和分子异质性。尽管如此，我们在这方面仍然存在着巨大的差距。 由于缺乏分子标记来识别和研究这些不同的亚型， 群体以及这些不同的星形胶质细胞如何调节神经元及其突触。我们最近 产生了一种新的转基因小鼠模型，选择性和鲁棒性标记特定的星形胶质细胞， 通过RNA和蛋白质分析，已经了解到这些星形胶质细胞是 高度和选择性地富含分泌蛋白Norrin。一种变异的norrin是一种罕见的 神经退行性疾病诺里氏病我们的初步研究强烈表明， Norrin在局部树突和棘的局部形成和/或维持中起重要作用。我们有 早期数据表明，这种星形胶质细胞norrin调节神经元棘密度和树突分支， 皮质层此外，我们的研究表明，这种星形胶质细胞亚群受到显着影响， 肌萎缩侧索硬化症在与杰克逊实验室的合作中，我们最近制造了一种诺里氏病 转基因小鼠，可以让我们探索这种蛋白质在体内和疾病中的功能。我们计划几个 了解星形胶质细胞norrin的生物学以及它如何改变树突/棘及其 在ALS和Norrie病中的神经变性的贡献。我们建议：1）评估皮质的作用， 星形胶质细胞Norrin在调节神经元树突和棘在体外和体内。这些研究将 证明Norrin在调节神经元中的作用，主要是通过树突和突触 开发和/或维护。2)确定星形胶质细胞突变Norrin是否足以改变 突触发育和/或维持。我们有了诺里病的第一个模型， 假设Norrin可以挽救这种星形胶质细胞神经退行性疾病。（3）调查损失 星形胶质细胞Norrin在运动神经元疾病中突触丢失和神经变性中的作用 模型和人类ALS。这些研究将评估norrin对几种突触损伤的作用。 ALS模型和人类ALS。总之，这些发现为研究这种新发现的 星形胶质细胞亚群在健康和疾病，包括潜在的产生细胞星形胶质细胞特异性 用于治疗多种神经系统疾病。