整合转录组关联研究和生物网络分析的阿尔茨海默病药物再利用。

IF 3.1 3区 医学 Q2 NEUROSCIENCES
Xin Wang, Meng Wang, Han Wang, Guosheng Yin, Yan Dora Zhang
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引用次数: 0

摘要

与分子机制相关的特定蛋白质沉积的积累是与阿尔茨海默病(AD)相关的许多大脑异常之一,AD是一种复杂的神经退行性疾病。目前还没有有效的治疗AD的方法。本研究试图通过基于生物网络的药物再利用策略来识别潜在的阿尔茨海默病治疗方法,重点关注针对阿尔茨海默病病理中重要蛋白质和生物学途径的药物。方法构建ad相关分子及其转录调控相互作用的综合生物学网络。这种计算方法整合了来自全基因组关联研究、多种ad相关磁共振成像(MRI)衍生表型、生物分子相互作用和基因表达谱的数据。结果构建的阿尔茨海默病亚调控网络显示,与对照组相比,阿尔茨海默病患者基因表达变化的转录因子之间存在显著相关性。该策略根据候选药物的作用机制对其进行优先排序,从而降低临床试验失败的风险,并提高与AD相关的患者预后。共有43种候选药物被确定,包括28种fda批准的药物,15种可能改变与AD病理重要方面相关的生物过程的实验和研究药物。Baricitinib和Gabapentin是针对ad相关的大脑皮层和海马区生物过程的有希望的候选药物。通过结合生物网络分析和mri驱动的全转录组关联研究,这种系统的药物再利用策略有望为阿尔茨海默病确定新的治疗方案,并为解决其他复杂的神经系统疾病提供潜在的启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Drug repurposing for Alzheimer's disease integrating transcriptome-wide association study and biological network analysis.

BackgroundThe accumulation of particular protein deposits connected to molecular mechanisms is one of the many brain abnormalities associated with Alzheimer's disease (AD), a complex neurodegenerative illness. There are currently no effective disease-modifying treatments for AD.ObjectiveThis study attempts to identify potential AD therapeutics through a biological network-based drug repurposing strategy, focusing on drugs targeting important proteins and biological pathways involved in AD pathology.MethodsA comprehensive biological network of AD-associated molecules and their transcription regulatory interactions is constructed. This computational approach integrates data from genome-wide association studies, multiple AD-related magnetic resonance imaging (MRI) derived phenotypes, biomolecular interactions, and gene expression profiles.ResultsThe constructed AD sub-regulatory network reveals significant correlations between transcription factors showing changed gene expression in AD patients relative to controls. This strategy prioritizes drug candidates based on their mechanisms of action, reducing the risk of clinical trial failures and enhancing patient outcomes related to AD. A total of 43 drug candidates have been identified, including 28 FDA-approved drugs, 15 experimental and investigational drugs that may alter biological processes pertaining to important facets of AD pathology. Baricitinib and Gabapentin emerge as promising candidates for targeting AD-related biological processes in the cerebral cortex and hippocampus regions.ConclusionsBy combining biological network analysis and MRI-driven transcriptome-wide association study, this systematic drug repurposing strategy demonstrates promise for identifying novel therapeutic options for AD and offers potential implications for addressing other complex neurological disorders.

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来源期刊
Journal of Alzheimer's Disease
Journal of Alzheimer's Disease 医学-神经科学
CiteScore
6.40
自引率
7.50%
发文量
1327
审稿时长
2 months
期刊介绍: The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.
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