Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing.
Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing.
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利用内表型和网络医学进行阿尔茨海默病药物的重新定位。
DOI：
10.1002/med.21709
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发表时间：
2020-11
影响因子：
13.3
通讯作者：
Cheng F
中科院分区：
文献类型：
--
作者：
Fang J;Pieper AA;Nussinov R;Lee G;Bekris L;Leverenz JB;Cummings J;Cheng F
经过二十年的 400 多项以“一种药物、一种靶点、一种疾病”范式为中心的临床试验，阿尔茨海默病 (AD) 仍然没有有效的疾病缓解疗法。 AD 固有的复杂性可能会挑战这种简化策略。网络医学的最新观察和进展进一步表明，AD 可能与其他疾病具有共同的潜在机制和中间病理表型或内表型。在这篇综述中，我们考虑了 AD 病理学、疾病共病、多效性和治疗开发，并构建了相关的内表型网络来指导未来的治疗开发。具体来说，我们讨论了 AD 中的六种主要内表型假说：淀粉样变性、tau 蛋白病、神经炎症、线粒体功能障碍、血管功能障碍和溶酶体功能障碍。我们进一步考虑这种内表型网络框架如何为患有 AD 或有 AD 风险的患者提供药物再利用和新候选治疗策略识别的计算和实验策略方面的进展。我们强调通过利用多组学数据在 AD 中进行基于内表型的药物发现的新机会。基因组学、转录组学、放射组学、药物基因组学和相互作用组学（蛋白质-蛋白质相互作用）的整合对于成功的药物发现至关重要。我们描述了 AD 药物发现的实验技术，包括人类诱导多能干细胞、转基因小鼠/大鼠模型以及基于群体的回顾性病例对照研究，这些技术可以与网络医学方法中的多组学相结合。总之，基于内表型的网络医学方法将促进 AD 治疗的发展，从而优化现有数据的有用性，并支持 AD 个性化医疗的患者异质性的深度表型分析。
Following two decades of more than 400 clinical trials centered on the “one drug, one target, one disease” paradigm, there is still no effective disease modifying therapy for Alzheimer’s disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how this endophenotype network framework can provide advances in computational and experimental strategies for drug-repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype-informed, drug discovery in AD, by exploiting multi-omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein-protein interactions) are essential for successful drug discovery. We describe experimental technologies for AD drug discovery including human induced pluripotent stem cells, transgenic mouse/rat models, and population-based retrospective case-control studies that may be integrated with multi-omics in a network medicine methodology. In summary, endophenotype-based network medicine methodologies will promote AD therapeutic development that will optimize the usefulness of available data and support deep phenotyping of the patient heterogeneity for personalized medicine in AD.
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影响因子：
14.9
作者：
Chatr-Aryamontri A;Oughtred R;Boucher L;Rust J;Chang C;Kolas NK;O'Donnell L;Oster S;Theesfeld C;Sellam A;Stark C;Breitkreutz BJ;Dolinski K;Tyers M
通讯作者：
Tyers M
影响因子：
25
作者：
Asai H;Ikezu S;Tsunoda S;Medalla M;Luebke J;Haydar T;Wolozin B;Butovsky O;Kügler S;Ikezu T
通讯作者：
Ikezu T
影响因子：
16.1
作者：
Banks, William A.
通讯作者：
Banks, William A.
晚期阿尔茨海默病研究中基因组变异的功能注释
影响因子：
5.8
作者：
Butkiewicz, Mariusz;Blue, Elizabeth E.;Bush, William S.
通讯作者：
Bush, William S.
影响因子：
5.9
作者：
Brilliant, Murray H.;Vaziri, Kamyar;McKay, Brian S.
通讯作者：
McKay, Brian S.