Identifying a new drug target for the treatment of Alzheimer's disease

确定治疗阿尔茨海默病的新药物靶点

• 批准号: 1916417
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1916417
• 关键词: Identifying; new; drug; target; treatment

Inflammation contributes to the progression of Alzheimer's disease (AD) and on-going research is establishing the NLRP3-inflammasome complex as one of the most important regulators of inflammation in AD. The NLRP3 inflammasome forms a molecular platform inside microglial cells, catalysing the activation of the protease caspase-1. Caspase-1 is responsible for converting the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) from an inactive to an active secreted form, which is recognised as a major contributor to a number of diverse diseases and key therapeutic target. Active caspase-1 is present in the brains of humans with AD, suggesting that NLRP3 may contribute to the human condition. NLRP3 is also central to the development of inflammation, pathology and memory deficits in a mouse model of AD. Anti-IL-1 drugs, such as the biologicals canakinumab and anakinra, do not easily penetrate the brain and there are no molecules known to directly target NLRP3 in clinical use. We have identified the volume regulated anion channel (VRAC), a Cl- channel in the plasma membrane, as an important regulator of the NLRP3 inflammasome, and a potential target to limit NLRP3-dependent inflammation. Here we hypothesise that VRAC contributes to the inflammation that underpins the pathological process of AD and therefore aim to establish VRAC as a therapeutic target for AD.

炎症有助于阿尔茨海默病(AD)的进展，正在进行的研究正在确定NLRP3-炎症体复合体是AD中最重要的炎症调节因子之一。NLRP3炎症体在小胶质细胞内形成一个分子平台，催化蛋白酶caspase-1的激活。Caspase-1负责将强有力的促炎细胞因子IL-1β(IL-1β)从非活性的分泌形式转化为活性的分泌形式，后者被认为是许多不同疾病的主要贡献者和关键的治疗靶点。在AD患者的大脑中存在活性的caspase-1，这表明NLRP3可能与人类的疾病有关。NLRP3也是阿尔茨海默病小鼠模型炎症、病理和记忆缺陷发展的核心。抗IL-1药物，如生物制品canakinumab和anakinra，不容易渗透到大脑，而且临床上还没有已知的直接针对NLRP3的分子。我们已经确定，体积调节阴离子通道(Vrac)是质膜上的一个氯离子通道，是NLRP3炎症体的重要调节因子，也是限制NLRP3依赖的炎症反应的潜在靶点。在这里，我们假设vrac参与了支持AD病理过程的炎症，因此旨在建立vrac作为AD的治疗靶点。