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.

项目总结 星形胶质细胞对中枢神经系统(CNS)的动态平衡和维持至关重要。他们 表现出大量的作用，如神经递质代谢，突触神经递质的调节 清除、细胞外离子缓冲、神经营养释放、免疫信号和血脑屏障 维修。毫不奇怪，不同区域的星形胶质细胞表现出不同的功能，以维持其 环境利基。在历史上，星形胶质细胞根据其神经解剖学被分为两组 灰质原浆星形胶质细胞和纤维性星形胶质细胞的定位和形态描述 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 神经元功能和分子的异质性。尽管如此，我们仍然存在着很大的差距 由于缺乏识别和研究这些不同亚型的分子标记，对这些不同亚型的了解 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，可以选择性而有力地标记特定的星形胶质细胞 成体中枢神经系统的亚群，通过RNA和蛋白质分析，了解到这些星形胶质细胞是 高度和选择性地富含一种分泌蛋白质，Norrin。Norrin的突变形式是一种罕见的 神经退行性疾病，诺里病。我们的初步研究强烈表明，星形胶质细胞 Norrin在局部树突和棘突的局部形成和/或维持中起重要作用。我们有 早期数据表明，这种星形细胞去甲肾上腺素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在 肌萎缩侧索硬化症。在与杰克逊实验室的合作下，我们最近产生了一种诺里病 转基因小鼠，可以让我们在体内和疾病中探索这种蛋白质的功能。我们计划了几个 了解星形胶质细胞去甲肾上腺素的生物学及其如何改变树突/棘突的方法 在肌萎缩侧索硬化症和诺里病中对神经退行性变的贡献。我们建议：1)评估皮质的作用 星形胶质细胞去甲肾上腺素在体内外调节神经元树突和棘突中的作用。这些研究将 证明去甲肾上腺素主要通过树突状细胞和突触来调节神经元 开发和/或维护。2)确定星形胶质细胞突变体Norrin是否足以改变 体内突触的发育和/或维持。我们有了第一个诺里病模型，并将测试 假设去甲肾上腺素可以挽救这种神经退行性疾病的星形胶质细胞。以及3)调查损失情况 星形胶质细胞去甲肾上腺素在运动神经元病突触丢失和神经变性中的作用 模特和人类肌萎缩侧索硬化。这些研究将评估去甲肾上腺素在突触损伤中的作用 肌萎缩侧索硬化模型和人类肌萎缩侧索硬化症。综上所述，这些发现为研究新发现的 星形胶质细胞亚群在健康和疾病中的作用，包括产生星形胶质细胞特异性细胞的可能性 几种神经疾病的治疗学。