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一种用于解析复杂疾病中细胞动力学和计算机辅助药物发现的深度生成模型。

A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases.

作者信息

Zheng Yumin, Schupp Jonas C, Adams Taylor, Clair Geremy, Justet Aurelien, Ahangari Farida, Yan Xiting, Hansen Paul, Carlon Marianne, Cortesi Emanuela, Vermant Marie, Vos Robin, De Sadeleer Laurens J, Rosas Ivan O, Pineda Ricardo, Sembrat John, Königshoff Melanie, McDonough John E, Vanaudenaerde Bart M, Wuyts Wim A, Kaminski Naftali, Ding Jun

机构信息

Quantitative Life Sciences, Faculty of Medicine & Health Sciences, McGill University, Montreal, Quebec, Canada.

Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.

出版信息

Nat Biomed Eng. 2025 Jun 20. doi: 10.1038/s41551-025-01423-7.

Abstract

Human diseases are characterized by intricate cellular dynamics. Single-cell transcriptomics provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in silico drug interventions. Here we introduce UNAGI, a deep generative neural network tailored to analyse time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modelling and screening. When applied to a dataset from patients with idiopathic pulmonary fibrosis, UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation using proteomics reveals the accuracy of UNAGI's cellular dynamics analysis, and the use of the fibrotic cocktail-treated human precision-cut lung slices confirms UNAGI's predictions that nifedipine, an antihypertensive drug, may have anti-fibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including COVID, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond idiopathic pulmonary fibrosis, amplifying its use in the quest for therapeutic solutions across diverse pathological landscapes.

摘要

人类疾病的特征是复杂的细胞动态变化。单细胞转录组学提供了关键见解,但在用于详细疾病进展分析和靶向计算机药物干预的计算工具方面,仍然存在持续的差距。在这里,我们介绍了UNAGI,这是一种专门用于分析时间序列单细胞转录组数据的深度生成神经网络。该工具捕捉了疾病进展背后复杂的细胞动态变化,增强了药物扰动建模和筛选。当应用于特发性肺纤维化患者的数据集时,UNAGI学习到了与疾病相关的细胞嵌入,加深了我们对疾病进展的理解,从而识别出潜在的治疗药物候选物。使用蛋白质组学进行验证揭示了UNAGI细胞动态分析的准确性,并且使用纤维化鸡尾酒处理的人类精密切割肺切片证实了UNAGI的预测,即抗高血压药物硝苯地平可能对人体组织具有抗纤维化作用。UNAGI的通用性扩展到包括COVID在内的其他疾病,展示了其适应性,并证实了其在解码特发性肺纤维化以外的复杂细胞动态变化方面具有更广泛的适用性,扩大了其在寻求跨多种病理情况的治疗解决方案中的应用。

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