Regulation of choroid plexus epithelial function by klotho

项目总结 与年龄相关的蛋白质和细胞功能的变化在整个大脑中都会发生。加深了对 当与年龄相关的事件变得病理性时，需要支持健康的大脑老化和发育 早期有效的神经退行性疾病治疗。在经历年龄的脑细胞中- 与结构和功能相关的损害，脉络丛上皮细胞作为一种具有 尚未开发的支持整个大脑实质的潜力。脉络丛上皮细胞高表达 Klotho蛋白质。Klotho的表达增加增强，但表达减少则损害神经元 跨物种和神经退行性疾病模型的记忆功能。最近的研究确定了一个 人类常见的增加蛋白质的Klotho多态变体对阿尔茨海默病具有保护作用 发育和病理学。而Klotho在脑实质细胞内和细胞上的作用表明它的作用 都是全脑的，对脑部Klotho的主要来源-脉络丛上皮细胞知之甚少。我们的 试点数据表明，细胞类型特异性klotho缺乏会影响寿命、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、营养和 对整个大脑的信号转导支持。它们还起到物理保护屏障的作用， 身体和大脑之间的交流中心。这项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角蛋白缺乏症的健康相关功能后果。 我们将用小鼠模型来验证Klotho缺乏症损害大脑这一中心假说 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表达在一生中对记忆的作用。 利用动物模型以及细胞和分子技术，目标二将确定脉络丛 Klotho缺乏症会改变上皮细胞的结构或功能。这项建议的意义在于 Klotho是一种对正常脉络丛至关重要的蛋白质，对理解Klotho的基本生物学有贡献 维持和支持健康脑实质所需的上皮细胞功能。我们是 独特的地理位置使本科生对研究和专注于医学的职业感兴趣 利用动物模型发现神经科学研究。这项提议在使用新动物方面很有创意 允许靶向操纵Klotho表达的模型，以及在研究脉络丛上皮时， 研究一种组织类型，具有未实现的潜力，以支持终身大脑健康。

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.