Role of ependyma in forebrain homeostasis

室管膜在前脑稳态中的作用

• 批准号: 9899335
• 负责人: Hooman Troy Ghashghaei
• 金额: $ 32.47万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899335
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Astrocytes; Attention; Biochemical; Biological Assay; Biological Markers; Blood Circulation; Blood Vessels; Brain; Cells; Cerebrospinal Fluid; Communicable Diseases; Defect; Dementia; Disease; Elderly; Ependyma; Ependymal Cell; Epithelial; Epithelium; Etiology; Filtration; Functional disorder; Genetic; Homeostasis; Human; Immune; Impaired cognition; In Vitro; Infection; Inflammation; Inflammatory; Lead; Life; Lymph; Lymphatic System; MARCKS gene; Maintenance; Maps; Measures; Mediating; Memory; Meninges; Metabolic; Modeling; Molecular; Mucins; Mus; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neuroimmune; Neurologic; Neurons; Pathologic; Pharmacology; Physiological; Plant Roots; Population; Probability; Production; Prosencephalon; Protein Isoforms; Proteomics; Publications; Publishing; Regulation; Research Proposals; Role; Signal Transduction; Stress; System; Testing; Tissue imaging; Tissues; Toxin; Waste Products; Wild Type Mouse; aged; aging brain; brain parenchyma; cognitive capacity; cognitive performance; conditioned fear; glymphatic system; healthy aging; imaging approach; inflammatory marker; interstitial; lymphatic vessel; monolayer; mouse model; new therapeutic target; normal aging; novel; public health relevance; response; spatial memory; therapeutic target; toxicant; trafficking; ventricular system

Project Description The high probability of breakdown in the functioning of the central nervous system (CNS) during late stages of aging, as in Alzheimer’s disease and various dementias is a major concern for the elderly. Triggers that initiate age-associated diseases and neurological conditions are for the most part unknown. A key to these associations could be the population of ependymal cells in the brain. Ependymal cells form a monolayer that functions as a barrier between the cerebrospinal fluid (CSF) and the overlying cellular compartments of the brain. As such, they regulate CSF production, circulation, and filtering, and thus ependymal cells are a key component of the newly described ‘glymphtic-lymphatic’ system. This system is purported to control CSF- vascular interactions in the brain parenchyma and thus contribute to the overall clearance of the brain of toxicants and metabolic byproducts and allow entry of immune cells into the brain. The ependymal layer appears damaged in the aged brain, yet whether the damage is caused by malfunctioning signals in the overlying CNS tissue, or if ependymal damage causes defects in neurons and glia in the CNS remain unknown. We have developed several genetic mouse models which suggest the ependymal layer may be the root of many problems in the brain interstitium related to various neurodegenerative diseases and during normal aging in the CNS. We will use these models to study this novel concept. Studies in our mouse models have revealed a previously unknown expression and clearance of mucins by ependymal cells in the CNS. Since mucins function to protect against inflammation and infectious diseases in other tissues, our results have led to the central hypothesis that mucin secretion by ependymal cells is required for maintenance and functional integrity of homeostasis in the forebrain during aging, and that disruption of mucin secretion can lead to aberrant function and disease in the CNS. Our project uses a variety of genetic mice, together with cellular, molecular, and biochemical approaches to test our hypothesis. Potential for Broader Impact: Our approaches to understand how aging affects the brain through its monolayer of ependymal cells have wide implications. Disruption of filtration and protective functions of ependymal cells may be the root of a range of pathological conditions that emerge during late stages of aging. Therefore, undertaking the basic cellular mechanisms that control aging of the brain is critical to understanding not only how healthy aging may be controlled by ependymal cells, but also how abnormalities in ependymal aging may lead to devastating diseases such as Alzheimer’s. Moreover, the mechanisms we study can be harnessed to develop novel aging therapeutics by targeting ependymal functions selectively.

项目描述 中枢神经系统（CNS）功能在晚期阶段崩溃的可能性很高， 衰老，如阿尔茨海默氏病和各种痴呆，是老年人的主要关注点。启动的触发器 与年龄有关的疾病和神经系统疾病大部分是未知的。一把钥匙 关联可能是大脑中室管膜细胞的数量。室管膜细胞形成单层， 作为脑脊液（CSF）和上覆的细胞隔室之间的屏障， 个脑袋因此，它们调节CSF的产生、循环和过滤，因此室管膜细胞是调节CSF分泌的关键。 新描述的“glymphtic-lymphatic”系统的组成部分。该系统旨在控制CSF- 脑实质中的血管相互作用，从而有助于脑的总体清除。 有毒物质和代谢副产品并允许免疫细胞进入大脑。室管膜 在老年人的大脑中似乎受到了损害，然而，这种损害是否是由大脑中的信号故障引起的， 覆盖CNS组织，或者如果室管膜损伤导致CNS中的神经元和神经胶质缺陷， 未知我们已经建立了几种遗传小鼠模型，这些模型表明室管膜层可能是 许多问题的根源在脑垂体有关的各种神经退行性疾病和在 中枢神经系统的正常老化。我们将使用这些模型来研究这个新概念。在我们的小鼠模型中的研究 已经揭示了CNS中室管膜细胞对粘蛋白的先前未知的表达和清除。 由于粘蛋白的功能是防止炎症和感染性疾病在其他组织，我们的研究结果 导致了中心假设，即室管膜细胞的粘蛋白分泌是维持所需的， 老化过程中前脑内稳态的功能完整性，以及粘蛋白分泌的破坏可导致 中枢神经系统的异常功能和疾病。我们的项目使用了各种基因小鼠，以及细胞， 分子和生物化学的方法来验证我们的假设。 潜在的更广泛的影响：我们的方法来了解衰老如何影响大脑，通过其 单层室管膜细胞具有广泛意义。过滤和保护功能的破坏 室管膜细胞可能是衰老后期出现的一系列病理状况的根源。 因此，研究控制大脑衰老的基本细胞机制对于理解 不仅室管膜细胞如何控制健康衰老，而且室管膜细胞的异常如何控制健康衰老， 衰老可能会导致老年痴呆症等毁灭性疾病。此外，我们研究的机制可以是 通过选择性地靶向室管膜功能来开发新的衰老疗法。