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Regulation of choroid plexus epithelial function by klotho

klotho对脉络丛上皮功能的调节

基本信息

批准号：
10291166
负责人：
Gwendalyn DiAnn King
金额：
$ 43.65万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291166
关键词：
AQP1 gene Adult Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Animal Model Atrophic Biology Brain Cell physiology Cells Cellular Structures Cellular biology Cerebrospinal Fluid Choroid Plexus Epithelium Communication Data Development Disease Elderly Epithelial Cells Event Exposure to Functional disorder Genetic Polymorphism Goals Health Hippocampus (Brain)Human Impairment Inflammatory Investigation Knowledge Life Literature Location Longevity Measures Mediating Medical Memory Memory Loss Memory impairment Methodology Modeling Molecular Mus Na(+)-K(+)-Exchanging ATPase Neurodegenerative Disorders Neuroglia Neurons Neurosciences Research Nutrient Oxidative Stress Pathologic Pathology Peripheral Phenotype Pilot Projects Positioning Attribute Production Property Proteins Regulation Research Research Personnel Role Signal Transduction Source Structure Structure of choroid plexus Synaptic Transmission Techniques Testing Therapeutic Time Tissues Transplantation Variant Water Work age related aging brain apolipoprotein E-4 base blood cerebrospinal fluid barrier brain cell brain health brain parenchyma career cell type chronic neurologic disease cohort experience high risk improved inflammatory milieu innovation insight interest klotho protein male mouse model novel novel therapeutics overexpression premature prevent protective effect protein expression stem cell niche therapeutic development undergraduate student

项目摘要

PROJECT SUMMARY Age-related changes to protein and thus cellular function occur across the brain. Increased understanding of when age-related events become pathological is required both to support healthy brain aging and to develop early and efficacious neurodegenerative disease therapeutics. Among the cells of the brain to experience age- related impairment to structure and function, the choroid plexus epithelial cells stand out as a tissue with untapped potential to support the entire brain parenchyma. Choroid plexus epithelial cells express high levels of Klotho protein. Increasing expression of Klotho enhances but decreasing expression impairs neuronal memory function across species and in models of neurodegenerative disease. Recent work determined that a common human polymorphic variant of Klotho that increases protein is protective against Alzheimer’s disease development and pathology. While Klotho action in and upon cells of the brain parenchyma indicates its effects are brain-wide, little is known about the primary source of brain Klotho, the choroid plexus epithelial cells. Our pilot data indicate that cell-type specific klotho-deficiency impacts longevity, memory, and choroid plexus cell structure and function. These data suggest that Klotho may effects cells throughout the brain because it is critical to choroid plexus epithelial cell activities. Choroid plexus epithelial cells provide physical, nutrient, and signal transduction support to the entire brain. They also function as a physical protective barrier and communication center between body and brain. The long-term goal of the proposed research is to understand the health-related functional consequences of age-related klotho-deficiency from choroid plexus epithelial cells. We will use mouse models to interrogate the central hypothesis that Klotho-deficiency impairs brain parenchyma by disrupting the function of the choroid plexus epithelial cells. In specific aim one, we will use mouse models to determine the role of choroid plexus-specific Klotho expression on memory across lifespan. Using animal models and cellular and molecular techniques, aim two will determine whether choroid plexus epithelial cell structure or function are altered by Klotho-deficiency. The significance of the proposal lies in contributions to understanding the basic biology of Klotho as a protein critical for the normal choroid plexus epithelial cell functions required to sustain and support healthy brain parenchyma across lifespan. We are uniquely situated to expose undergraduate students interested in research and medically focused careers discovery neuroscience research using animal models. The proposal is innovative in its use of novel animal models to allow targeted manipulation of Klotho expression and, in studying the choroid plexus epithelia, studies a tissue-type with unrealized potential to support brain health across lifespan.

项目概要与年龄相关的蛋白质和细胞功能的变化发生在整个大脑中。增进了解当与年龄相关的事件变得病理性时，既需要支持健康的大脑老化，又需要发展早期有效的神经退行性疾病治疗方法。在经历年龄的大脑细胞中—— 与结构和功能相关的损伤，脉络丛上皮细胞作为具有支持整个大脑实质的未开发潜力。脉络丛上皮细胞高水平表达 Klotho 蛋白。增加 Klotho 的表达会增强神经元，但减少表达会损害神经元跨物种和神经退行性疾病模型中的记忆功能。最近的工作确定了 Klotho 的常见人类多态性变体可增加蛋白质，可预防阿尔茨海默病发育和病理学。虽然 Klotho 在脑实质细胞内和细胞上的作用表明了其影响是全脑的，但人们对大脑 Klotho 的主要来源——脉络丛上皮细胞知之甚少。我们的试验数据表明，细胞类型特异性 klotho 缺陷会影响寿命、记忆力和脉络丛细胞结构和功能。这些数据表明 Klotho 可能会影响整个大脑的细胞，因为它对脉络丛上皮细胞活性至关重要。脉络丛上皮细胞提供物理、营养和信号转导支持整个大脑。它们还起到物理保护屏障的作用身体和大脑之间的通讯中心。拟议研究的长期目标是了解脉络丛上皮细胞与年龄相关的 klotho 缺陷导致的健康相关功能后果。我们将使用小鼠模型来检验 Klotho 缺陷会损害大脑的中心假设通过破坏脉络丛上皮细胞的功能来破坏实质。在具体目标一中，我们将使用小鼠模型以确定脉络丛特异性 Klotho 表达对整个生命周期记忆的作用。使用动物模型和细胞和分子技术，目标二将确定脉络丛是否 Klotho 缺陷会改变上皮细胞的结构或功能。该提案的意义在于对理解 Klotho 作为对正常脉络丛至关重要的蛋白质的基础生物学的贡献在整个生命周期中维持和支持健康的脑实质所需的上皮细胞功能。我们是地理位置独特，可以吸引对研究和医学职业感兴趣的本科生使用动物模型发现神经科学研究。该提案的创新之处在于使用了新颖的动物允许有针对性地操纵 Klotho 表达的模型，并在研究脉络丛上皮细胞时，研究一种具有未实现的潜力的组织类型，以支持整个生命周期的大脑健康。