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疫情的方法。这个关键角色是自然的。早在当前的危机之前， CTSA中心致力于翻译，建立多学科的调查人员和社区团队 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，以及用于诊断和治疗的颠覆性技术。在本提案中，我们 建立在我们中心积极参与有意义的临床试验的基础上（例如，NIH Remdesivir RCT）， 创建COVID-19患者的生物标本库，机构承诺和筹款， 一个350万美元的试点基金分配，一个强大的和可访问的临床数据库存储库，以及正在进行的 NCAT支持的CTSA合作创新奖（J.克雷格文特尔研究所的联盟， UCSD、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的新兴信息学框架， 通过综合数据分析，我们将把参加各种试验的COVID-19患者的临床数据与 在疾病的各个阶段，先天性和适应性免疫的创新体外评估， 在SARS-CoV-2病理学中仍然知之甚少，从患者生物标本中获得，以获得机制 在系统层面深入了解COVID-19发病机制。先天免疫和适应性免疫尤其 与COVID-19疾病发病机制相关，因为它们在COVID-19疾病的所有阶段都发挥着关键但独特的作用， 疾病（初始组织-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;最终，保护性免疫）。的 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COVID-19疫情相关的反应，迄今为止无法观察到。使用Hi-DAFi进行质量分析 流式细胞术分析，用于单细胞转录组学分析的经验证的信息学管道，以及尖端的 统计数据集成和机器学习策略与可用的临床数据联系在一起， 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， 疾病介导因素，如年龄，健康差异，以及其他疾病或条件的存在，如 肥胖这些信息将有助于关键的努力，以针对新的疗法，并可能确定特异质 个体生理变量使某些似乎没有已知合并症的患者 易受严重COVID-19疾病的影响。最后，UCI中心与两个区域之间的强大连接 和国家网络（例如，BRAID，5个UC CTSA和NCATS试验创新网络的联盟） 将提供一个前所未有的机会，迅速传播临床相关的发现，并使 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，他们的才能和洞察力。

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.