Astrocyte-secreted chaperones as a non-cell autonomous form of neuronal protection in Alzheimer's disease

星形胶质细胞分泌的伴侣作为阿尔茨海默氏病神经元保护的非细胞自主形式

基本信息

批准号：
MR/N022696/1
负责人：
Maria Jimenez-Sanchez
金额：
$ 123.88万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN022696%2F1
关键词：
Astrocyte secreted chaperones non cell

项目摘要

Currently, more than 46 million people worldwide and 850,000 people in the UK are living with dementia and Alzheimer's disease, a number that is expected to double every 20 years. Despite many efforts to find new disease-modifying therapies for this disease, recent clinical trials have failed to show significant benefits and currently patients are only treated with drugs that alleviate disease symptoms. Traditionally, drug discovery strategies have focused on neurons as the main targets in Alzheimer's and other brain disorders. In the brain, neurons are responsible for processing information, learning and memory, while other specialized brain cells called glial cells are necessary to maintain neuron health and to aid neuron function. To be able to design effective therapeutic strategies for Alzheimer's disease, we need to investigate not only how neurons become dysfunctional but also to better understand what is the contribution of glial cells to the degeneration of neurons and the disease progression. The aim of this project is to investigate how astrocytes, the most abundant type of glial cell, can protect neurons in Alzheimer's disease. If we are able to identify which are the factors released from astrocytes that mediate neuroprotection, we will be able to design effective therapeutic tools.This research program will be carried out at the Maurice Wohl Clinical Neuroscience Institute, a newly built highly interdisciplinary neuroscience center at King's College London. We have established complementary collaborations that will enable us to employ a number of models of Alzheimer's disease, including mouse neuron and glia cell cultures, mouse brain slices and human neurons derived from induced pluripotent stem cells from patients. Using these models, we will investigate what are the factors released from astrocytes that affect the accumulation of abnormal proteins in brain and we will determine how these factors can protect Alzheimer's disease neurons from dying. Our findings will provide pre-clinical evidence to support follow up therapeutic studies.This proposal will explore the potential benefits of increasing astrocyte-released factors as a potential therapeutic strategy to prevent loss of neuron function in Alzheimer's disease. This is a novel avenue of research, which could have a significant impact on our understanding of neurodegenerative mechanisms and that may identify new ways to treat Alzheimer's disease.

目前，全世界有超过4600万人，英国有85万人患有痴呆症和阿尔茨海默氏病，这一数字预计每20年将翻一番。尽管为这种疾病寻找新的疾病改良疗法的努力，但最近的临床试验未能显示出很大的好处，目前仅接受减轻疾病症状的药物的治疗。传统上，药物发现策略集中在神经元上是阿尔茨海默氏症和其他脑部疾病的主要靶标。在大脑中，神经元负责处理信息，学习和记忆，而其他称为神经胶质细胞的专业脑细胞对于维持神经元健康和帮助神经元功能是必要的。为了能够为阿尔茨海默氏病设计有效的治疗策略，我们不仅需要研究神经元如何发挥功能障碍，而且还需要更好地了解神经胶质细胞对神经元变性和疾病进展的贡献是什么。该项目的目的是研究星形胶质细胞（最丰富的神经胶质细胞）如何保护阿尔茨海默氏病中的神经元。如果我们能够确定哪些是介导神经保护的星形胶质细胞中释放的因素，我们将能够设计有效的治疗工具。该研究计划将在莫里斯·沃尔（Maurice Wohl）临床神经科学研究所（Maurice Wohl Clinical Neuroscience Institute）进行，这是一个新建造的高度跨学科的神经科学中心，位于国王伦敦国王学院。我们已经建立了互补的合作，使我们能够采用许多阿尔茨海默氏病模型，包括小鼠神经元和神经胶质细胞培养物，小鼠脑切片和人类神经元，这些神经元来自患者的诱导多能干细胞。使用这些模型，我们将研究影响大脑中异常蛋白质积累的星形胶质细胞释放的因素，我们将确定这些因素如何保护阿尔茨海默氏病神经元免受死亡的死亡。我们的发现将提供临床前证据，以支持后续治疗研究。该提案将探讨增加星形胶质细胞释放因素的潜在好处，以此作为防止阿尔茨海默氏病中神经元功能丧失的潜在治疗策略。这是一种新的研究途径，它可能会对我们对神经退行性机制的理解产生重大影响，并且可以确定治疗阿尔茨海默氏病的新方法。