Identification of the neuronal receptor for the cognitive-enhancing soluble klotho ligand

衰老是认知能力下降的主要风险因素，包括学习和记忆方面的问题。在这个项目中，我们将重点研究抗衰老蛋白质klotho，它具有增强认知的特性。Klotho增强神经细胞的功能，特别是学习和记忆所需的突触的变化。此外，Klotho还保护神经细胞免受氧化损伤，氧化损伤会增加衰老的大脑。Klotho的这些认知增强特性是通过Klotho与神经细胞表面的未知受体相互作用而实现的。我们假设，人类神经细胞上Klotho受体的识别和表征将为认知增强策略提供新的机会，以对抗与年龄相关的认知功能障碍。该项目的目标是在探索Klotho的认知增强潜力方面采取必要的后续步骤：1)确定Klotho在人类神经细胞表面的受体；2)验证细胞和脑组织中的Klotho受体；以及3)确定Klotho受体如何与神经细胞功能的有益变化联系起来。我们将使用一系列最先进的生化和细胞生物学方法来解决这些目标，并通过使用人类干细胞来源的神经元和死后的人脑材料，将我们的发现与人类大脑中看到的变化联系起来。Klotho受体的识别将开辟新的药理学方法来模拟Klotho在年龄相关认知功能障碍中的活动。

Ageing is the main risk factor for cognitive decline, including problems with learning and memory. In this project we will focus on the anti-ageing protein, klotho, which has cognitive-enhancing properties. Klotho enhances the function of nerve cells, particularly the changes in synapses that are required for learning and memory. In addition, klotho protects nerve cells against oxidative damage which increases in the aged brain. These cognitive-enhancing properties of klotho are mediated by klotho interacting with an unknown receptor on the surface of nerve cells. We hypothesise that identification and characterisation of the receptor for klotho on human nerve cells will provide new opportunities for cognitive-enhancing strategies to combat age-related cognitive dysfunction. The objectives of this project are to take the essential next steps in exploring the cognitive-enhancing potential of klotho by: 1) identifying the receptor for klotho on the surface of human nerve cells; 2) validating the receptor for klotho in cells and brain tissue; and 3) determining the how the klotho receptor links to the beneficial changes in nerve cell function. We will use a range of state-of-the-art biochemical and cell biological approaches to address these objectives, and will link our findings to changes seen in the human brain by using human stem cell-derived neurons and post mortem human brain material. Identification of the klotho receptor will open the way to novel pharmacological approaches to mimic klotho activity in age-associated cognitive dysfunction.