WNT signaling: biomarker and target evaluation in Alzheimer's disease

WNT 信号传导：阿尔茨海默病的生物标志物和靶标评估

• 批准号: MR/L501505/1
• 负责人: Simon Lovestone
• 金额: $ 28.05万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL501505%2F1
• 关键词: WNT; signaling; biomarker; target; evaluation

The invariant failure of Biopharmaceutical pipelines to modify Alzheimer'sdisease (AD) progression indicates the need for new creative solutions beyondcurrently active areas of genetics, amyloid-ß, and Tau pathology. Very recent workfrom our groups and others indicate that novel elements of the canonical and noncanonical WNT signaling pathways could be targeted to modify and monitor ADprogression.In this project we will use multidisciplinary approaches, including brain oriented drug screening, a novel proprietary mouse model of AD, new genetic and pharmacological tools for modulation of WNT/GSK3 and WNT/JNK pathways, humanblood samples from our and the IMI/EMIF platform to identify novel biomarkers of AD progression and a pilot study on metabolomics, to explore the impact on AD ofnovel WNT elements including but not limited to clusterin, DKK1 and Nrf2.Our results in this pathfinder phase with the identification of new candidate targets and drugs for clinical studies will pave the way to therapeutic innovations inthe long-term programme. Indeed, several Biopharma companies have initiated drug development programs aimed at targeting certain components of the WNT signaling pathway, including ligands and other small molecule regulators of Axin1 and GSK-3, and Nrf2 that will be interested in our findings.

生物制药管道在改变阿尔茨海默病（AD）进展方面的不变失败表明需要超越目前活跃的遗传学、淀粉样蛋白和Tau病理学领域的新的创造性解决方案。本课题组和其他研究人员最近的工作表明，经典和非经典WNT信号通路的新元件可以被靶向修饰和监测AD的进展。在本项目中，我们将使用多学科的方法，包括脑导向药物筛选，一种新型的AD专有小鼠模型，用于调节WNT/GSK 3和WNT/JNK通路的新的遗传和药理学工具，来自我们和IMI/EMIF平台的人类血液样本，以鉴定AD进展的新生物标志物和代谢组学的初步研究，以探索新WNT元件对AD的影响，包括但不限于clusterin，DKK 1和Nrf 2。我们在这个开拓者阶段的结果，确定了新的候选靶点和临床研究的药物，将为长期计划中的治疗创新铺平道路。事实上，几家Bioproma公司已经启动了药物开发计划，旨在靶向WNT信号通路的某些组分，包括Axin 1和GSK-3的配体和其他小分子调节剂，以及对我们的发现感兴趣的Nrf 2。

项目成果

NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology.

• DOI: 10.1016/j.redox.2017.07.006
• 发表时间: 2017-10
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Rojo AI;Pajares M;Rada P;Nuñez A;Nevado-Holgado AJ;Killik R;Van Leuven F;Ribe E;Lovestone S;Yamamoto M;Cuadrado A
• 通讯作者: Cuadrado A