Development of data driven and AI empowered systems biology to study human diseases

项目摘要 系统生物学模型为研究生物过程的功能影响提供了一种有效的方法， 复杂的疾病系统尽管在基于微分方程的系统生物学方面有大量的知识， 尽管在建立人类疾病动态模型方面取得了进展，但仍存在重大差距。 本质上，在疾病状态下，非线性依赖性中涉及的参数在很大程度上是未知的。 条件和系统生物学模型总是在一个简化的范式，这几乎不能 描述复杂的疾病系统。大量的单细胞、空间或组织多组学数据 已经证明从疾病组织中获得的DNA具有在细胞上传递信息的潜力 功能状态及其潜在的表型开关。因此，先进的系统生物学模型和 计算工具是迫切需要授权可靠的表征生物过程及其 在疾病中的功能作用。我们的初步数据包括（1）一个新的计算 一种利用转录组学数据近似系统生物学模型的方法，以及（2）计算原理， 利用组学数据对动力学系统进行近似，形成了 这个项目在这个MIRA项目中，我提议开发一套新颖的计算方法，即系统生物学 模型和定量指标，带来以下未满足的能力：（1）计算框架， 使用组学数据建立动态模型，这将使以下分析能够研究复杂疾病 系统：（i）评估生物过程的样品活性;（ii）扰动分析，以评估生物过程的活性。 生物特征或模型结构对系统的影响，可以作为新的药物靶点，以及（iii） 评估系统如何通过疾病进展演变;（2）基于自然语言处理的 提取生物功能和关系以自动建立系统的上下文特定知识 结构和组成部分;（3）计算原理和理论的科学文献数据; 组学数据中动态系统的可识别性和数学表示。通过实施这些 方法纳入多组学数据分析，我们计划解决以下突出的生物学问题：（i） 鉴定对不同疾病中的代谢变化具有高度影响的分子特征，（ii） （iii）代谢和其他生物学功能的转录调节， 过程，（iv）遗传变异的功能注释，以及（v）生化变异的评估。我们将 还开发了泛疾病中代谢和其他变异的新知识表示和转移 分析，以帮助更好地了解基本疾病病理，促进精准医疗 研究，包括新生物标志物的预测和验证，营养推荐和药物再利用。 成功执行拟议的研究将提供一套计算能力，以量化和 研究可被生物医学研究界广泛利用的一般生物过程。

Project Summary Systems biology models provide an effective way to study the functional impact of biological process within complex disease system. Despite a plethora of knowledge on the differential equation-based systems biology model have gained, there are still major gaps in raising dynamic models within the context of human diseases. Essentially, the parameters involved in the non-linear dependencies are largely unknown under disease conditions and the systems biology models are always within a reductionist paradigm, which can hardly characterize the complicated disease system. The large amount of single-cell, spatial or tissue multi-omics data obtained from disease tissue has been proven to be endowed with the potential to deliver information on a cell functioning state and its underlying phenotypic switches. Hence, advanced systems biology models and computational tools are in pressing need to empower reliable characterization of biological processes and their functional roles in disease by using multi-omics data. Our preliminary data include (1) a new computational method to approximate systems biology model using transcriptomics data, and (2) computational principles to approximate dynamic system by using omics data, which form the methodology and theoretical foundations of this project. In this MIRA project, I proposed to develop a suite of novel computational methods, systems biology models and quantitative metrics to bring the following unmet capabilities: (1) A computational framework to establish dynamic models using omics data, which will enable the following analyses to study a complex disease system: (i) assessing sample-wise activity of biological processes; (ii) perturbation analysis to evaluate the impacts of biological features or model structures to the system, which could serve as new drug targets, and (iii) evaluating how the system evolve through disease progression; (2) A natural language processing-based extraction of biological functions and relations to automatically establish context specific knowledge of system structure and components from scientific literature datal; and (3) computational principles and theories of the identifiability and mathematical representation of dynamic systems in omics data. By implementing these methods into multi-omics data analysis, we plan to address the following outstanding biological questions: (i) identification of molecular features with high impact to metabolic variations in different diseases, (ii) the role of metabolism in fueling epigenetic regulation, (iii) transcriptional regulation of metabolism and other biological processes, (iv) functional annotation of genetic variations, and (v) assessment of biochemical variations. We will also develop novel knowledge representation and transfer of metabolic and other variations in pan-disease analysis to aid in better understanding of the basic disease pathology and promote the precision medicine research, including prediction and validation of new biomarkers, nutrition recommendation, and drug repurposing. Successful execution of the proposed research will provide a suite of computational capabilities to quantify and study general biological processes that could be broadly utilized by the biomedical research community.