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转化研究工作，开发新的 应对 COVID-19 大流行的方法。这个关键角色是自然而然的。早在当前的危机发生之前， CTSA 中心致力于翻译、建立由研究者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 变革性信息学以及诊断和治疗的颠覆性技术。在这个提案中，我们 以我们中心积极参与有意义的临床试验（例如 NIH Remdesivir RCT）为基础， 创建 COVID-19 患者生物样本库、机构承诺和筹款 350 万美元的试点基金分配、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（J. Craig Venter 研究所的联盟， 加州大学圣地亚哥分校 (UCSD)、加州大学尔湾分校 (UCI) 和斯坦福大学）专注于流式细胞术分析的人工智能方法 数据。使用监督广义典型相关性的新兴信息学框架 综合数据分析，我们将把参加各种试验的 COVID-19 患者的临床数据联系起来 在疾病的各个阶段，对先天性和适应性免疫进行创新的体外评估，这是一个领域 对 SARS-CoV-2 病理学仍知之甚少，从患者生物样本中获取以获得机制 在系统层面对 COVID-19 发病机制的见解。先天性和适应性免疫尤其重要 与 COVID-19 疾病发病机制相关，因为它们在疾病的各个阶段都发挥着关键但独特的作用 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，可能在病毒血症水平下降很久之后；以及最终的保护性免疫力）。的 当前 CCIA 新型流式细胞术信息学研究能够阐明动态细胞免疫 迄今为止无法观察到的与 COVID-19 大流行相关的反应。使用 Hi-DAFi 进行弥撒 细胞计数分析、用于单细胞转录组学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我们将要获得的可用临床数据相关联 能够发现细胞生物标志物与疾病状态、特定疗法之间的新关联，以及 疾病介导因素，例如年龄、健康差异以及其他疾病或状况的存在，例如 肥胖。这些信息将有助于针对新疗法的关键努力，并可能识别特殊的治疗方法 个体生理变量使某些似乎没有已知合并症的患者更容易 容易感染严重的 COVID-19 疾病。最后，UCI 中心与两个区域之间的牢固连接 和国家网络（例如，BRAID、5 个 UC CTSA 的联盟和 NCATS 试验创新网络） 将提供前所未有的机会来快速传播临床相关发现并让 许多临床医生和科学家的才华和洞察力为结束这一流行病不懈努力。

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.