Regulation of choroid plexus epithelial function by klotho

项目摘要 与蛋白质相关的变化，从而细胞功能发生在整个大脑中。更加了解 当与年龄有关的事件成为病理性的，是需要支持健康的大脑老化和发展 早期和有效的神经变性疾病治疗剂。在大脑细胞中体验年龄- 脉络丛上皮细胞与结构和功能相关的损伤， 支撑整个脑实质的潜力脉络丛上皮细胞表达高水平 Klotho蛋白Klotho表达增加增强但表达减少损害神经元 在不同物种和神经退行性疾病模型中的记忆功能。最近的研究表明， Klotho的一种常见的人类多态性变体，它增加了蛋白质对阿尔茨海默病的保护作用 发育和病理学。而Klotho在脑实质细胞内和脑实质细胞上的作用表明其作用 虽然Klotho是全脑的，但对脑Klotho的主要来源脉络丛上皮细胞知之甚少。我们 试验数据表明，细胞类型特异性klotho缺陷影响寿命、记忆和脉络丛细胞 结构和功能。这些数据表明，Klotho可能会影响整个大脑的细胞，因为它是 对脉络丛上皮细胞活动至关重要。脉络丛上皮细胞提供物理，营养， 信号传导支持整个大脑。它们还起到物理保护屏障的作用， 身体和大脑之间的沟通中心。这项研究的长期目标是了解 来自脉络丛上皮细胞的与年龄相关的klotho缺陷的健康相关功能后果。 我们将使用小鼠模型来质疑Klotho缺乏症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表达对整个寿命期记忆的作用。 利用动物模型和细胞分子技术，目的二将确定脉络丛是否 上皮细胞结构或功能因Klotho缺乏而改变。该提案的意义在于 对了解Klotho作为正常脉络丛关键蛋白的基础生物学的贡献 上皮细胞功能所需的维持和支持健康的脑实质的寿命。我们 独特的地理位置，让对研究和医学职业感兴趣的本科生 使用动物模型进行神经科学研究。该提案在使用新动物方面具有创新性 模型，以允许Klotho表达的靶向操作，在研究脉络丛上皮细胞， 研究一种具有未实现潜力的组织类型，以支持整个生命周期的大脑健康。

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.