THE SEARCH FOR COVID-19 PREVENTION AND CURE: ADDRESSING THE CRITICAL ROLE OF INNATE/ADAPTIVE IMMUNITY BY INTEGRATING NOVEL INFORMATICS, TRANSLATIONAL TECHNOLOGIES, AND ONGOING CLINICAL TRIAL RESEARCH

各个CTSA中心正在领导国家临床和翻译研究工作，开发新的 应对新冠肺炎大流行的方法。这一关键角色是自然而然的。早在当前危机之前， CTSA中心致力于翻译，建立由调查人员和社区组成的多学科团队 合作伙伴，克服监管负担，确保临床和人类研究的质量，开发 变革性的信息学，以及诊断和治疗的颠覆性技术。在这项提案中，我们 在我们中心积极参与有意义的临床试验(例如，NIH Remdesivir RCT)的基础上，早期 从新冠肺炎患者中创建生物脊髓库，机构承诺和筹款，导致 到350万美元的试点资金分配、强大且可访问的临床数据库存储库，以及正在进行的 NCATS支持的CTSA协作创新奖的工作(J.Craig Venter研究所的联盟， UCSD、UCI和Stanford)专注于用于流式细胞术分析的人工智能方法 数据。使用新兴的信息学框架--有监督的广义典型相关 综合数据分析，我们将把参加各种试验的新冠肺炎患者的临床数据联系起来 在疾病的不同阶段，通过创新的先天和获得性免疫的体外评估，一个领域 在SARS-CoV-2病理学方面仍然知之甚少，从患者的生物标本中获得机制 在系统水平上对新冠肺炎发病机制的洞察。特别是先天免疫和获得性免疫。 与新冠肺炎疾病的发病机制有关，因为它们在疾病的各个阶段都发挥着关键但不同的作用 疾病(最初的组织-病毒相互作用；全身反应；细胞介导的细胞因子风暴导致多- 器官衰竭和死亡，很可能是在病毒血症水平下降很久之后；最终是保护性免疫)。这个 目前CCIA新的流式细胞术信息学研究允许阐明动态细胞免疫 与新冠肺炎大流行相关的反应，到目前为止还看不到。使用Hi-DAFi进行质量管理 细胞学分析、用于单细胞转录分析的经过验证的信息学管道，以及尖端技术 统计数据集成和机器学习策略与可用的临床数据绑定在一起，我们将 能够发现细胞生物标记物和疾病状态、特定治疗方法之间的新关联，以及 疾病中介因素，如年龄、健康差距和其他疾病或状况的存在，如 肥胖。这些信息将有助于针对新疗法的关键努力，并可能确定特殊的 个体生理变量使某些似乎没有已知合并症的患者更多 易患严重的新冠肺炎病。最后，UCI枢纽和地区中心之间的强大联系 和国家网络(例如，Braid、5个UC CTSA的联盟和NCATS试验创新网络) 将提供一个前所未有的机会来迅速传播临床相关的发现并参与 许多临床医生和科学家为结束这一流行病而不知疲倦地工作的才华和洞察力。

Individual CTSA hubs are leading the national clinical and translational research efforts in developing new approaches to address the COVID-19 pandemic. This crucial role was natural. Long before the current crisis, CTSA hubs were committed to translation, building multidisciplinary teams of investigators and community partners, overcoming regulatory burdens, ensuring quality in clinical and human research, developing transformative informatics, and disruptive technologies for diagnostics and therapeutics. In this proposal, we build on our center’s active participation in meaningful clinical trials (e.g., the NIH Remdesivir RCT), the early creation of a biospecimen repository from COVID-19 patients, institutional commitment and fundraising that led to a $3.5 million pilot fund distribution, a robust and accessible clinical database repository, and the ongoing work of an NCATS-supported CTSA Collaboration Innovation Award (a coalition of the J. Craig Venter Institute, UCSD, UCI, and Stanford) focused on artificial intelligence approaches for the analysis of flow cytometry data. Using the emerging informatics framework of supervised generalized canonical correlation for integrative data analysis, we will link clinical data from COVID-19 patients enrolled in a variety of trials and at various stages of disease with innovative in vitro evaluation of innate and adaptive immunity, an area still poorly understood in SARS-CoV-2 pathology, obtained from patient biospecimens to obtain mechanistic insights of COVID-19 pathogenesis at a systems level. Innate and adaptive immunity are particularly relevant to COVID-19 disease pathogenesis because they play key, but distinct, roles at all phases of the illness (initial tissue-virus interaction; systemic responses; the cell-mediated cytokine storm leading to multi- organ failure and death, likely long after levels of viremia have fallen; and, ultimately, protective immunity). The current CCIA novel flow cytometry informatics research permits elucidation of dynamic cellular immune responses related to the COVID-19 pandemic that were heretofore unobservable. Using Hi-DAFi for mass cytometry analysis, validated informatics pipelines for single cell transcriptomics analysis, and cutting-edge statistical data integration and machine learning strategies tied back to the available clinical data we will be able to discover novel associations between cellular biomarkers and disease state, a particular therapy, and disease mediating factors such as age, health disparities, and the presence of other diseases or conditions like obesity. This information will aid in critical efforts to target new therapies and possibly identify idiosyncratic individual physiologic variables that render certain patients who seem to have no known comorbidities more vulnerable to severe COVID-19 disease. Finally, the robust connection between the UCI hub and both regional and national networks (e.g., BRAID, the coalition of the 5 UC CTSAs, and NCATS Trial Innovation Network) will provide an unprecedented opportunity to rapidly disseminate clinically relevant discoveries and engage the talent and insight of the many clinicians and scientists working tirelessly to end this pandemic.