Temporal Transcriptomics in Hospitalized COVID-19 Patients from Disparately Impacted Ancestral Groups for Therapeutic Discovery

项目摘要 SARS-CoV-2是一种引起COVID-19的新型冠状病毒，这种疾病已感染了超过4600万人， 到2020年10月31日，死亡人数超过120万。美国是全球病例数（> 920万）和死亡率（> 23万）最高的国家。 最近全国各地的每日病例和住院率都创下了纪录。这一点尤其 新墨西哥州（NM）的情况也是如此，那里的病例和住院人数再次激增。现在人们认识到， 少数群体，即，非裔美国人、西班牙裔美国人和美国印第安人/阿拉斯加原住民（AI/AN） 从COVID-19预防。新墨西哥州拥有最高比例的西班牙裔血统，也是最大的 AI/AN人群，这两组分别占累积病例的47%和26%。后 调整人口规模后，AI/AN组的累积病例率高出3.3倍， 住院率和10.6倍的年龄调整死亡率。作为唯一的学术医疗中心， 在该州的一级创伤中心，新墨西哥州大学医院发挥了主要作用 在照顾新冠肺炎患者方面。联海特派团是北卡罗来纳州及周边地区的初级和三级保健转诊中心。 地区，包括纳瓦霍族和其他部落的土地。因此，我们处于独特的地位， 关于COVID-19疾病严重程度和死亡率增加的分子基础的重要知识空白 在受影响的祖先群体中。2月中旬，UNM全球卫生中心组织了一次 多学科的研究小组，以应对COVID-19的挑战。截至10月31日， 招募并随访了167名住院的COVID-19患者， 在计划的三年研究中的影响。实验策略与我们正在进行的R01研究相似， 非洲儿童利用mRNA-Seq来确定新的治疗靶点（PI：Perkins）。state-of-the-art 我们实验室中的方法和建模工作将用于创建解决方案， COVID-19患者的结果。这将通过跟踪非重症和重症COVID-19患者来实现 从不同的祖先群体中成功地完成三个具体目标：1）确定 SARS-CoV-2病毒载量动态对疾病严重程度的影响，2）鉴定 介导疾病的严重程度，以及3）确定FDA批准的调节基因网络的优先化合物 用于未来的临床试验。在很短的时间内，我们已经产生了 广泛的病毒载量动态数据，并确定了新的基因网络与目标化合物的匹配。我们 目前的数据显示，AI/AN血统的个体在10岁以下的人群中具有显著更高和持久的病毒载量。 外周血和更严重的疾病，尽管与其他组的共病因素相当。的 建议的调查有直接的翻译影响，特别是在不成比例地影响祖先 通过定义宿主对SARS-CoV-2的免疫反应，确定用于风险评估的生物标志物， 预后和疾病进展，以及促进药物再利用以降低疾病严重程度和死亡率。

PROJECT SUMMARY SARS-CoV-2 is a novel coronavirus which causes COVID-19, a disease that has infected >46M people resulting in >1.2M deaths by 31 October 2020. The US has the highest global case count (>9.2M) and mortality (>230K) with recent record-setting daily cases and hospitalization rates across the country. This has been particularly true for New Mexico (NM) where cases and hospitalizations are surging again. It is now recognized that certain minority groups, i.e., African Americans, Hispanics, and American Indians/Alaska Natives (AI/AN), suffer disproportionally from COVID-19. NM has the highest proportion of Hispanic ancestry, and one of the largest AI/AN populations, with these two groups representing 47% and 26% of the cumulative cases, respectively. After adjusting for population size, the AI/AN group has 3.3-fold higher cumulative case rates, 7.9-fold higher hospitalizations, and 10.6-fold higher age-adjusted mortality rates. As the only academic medical center and Level 1 Trauma Center in the state, the University of New Mexico Hospital (UNMH) has played a principal role in caring for patients with COVID-19. UNMH is the primary tertiary care referral center for NM and surrounding regions, including the Navajo Nation and other tribal lands. As such, we are uniquely positioned to address important gaps-in-knowledge about the molecular basis of increased COVID-19 disease severity and mortality in disproportionally affected ancestral groups. In mid-February, the UNM Center for Global Health assembled a multidisciplinary group of investigators to address the challenges of COVID-19. As of 31 October, we have recruited and followed 167 hospitalized patients with COVID-19, offering an opportunity for rapid translational impact within the planned three-year study. The experimental strategy parallels our ongoing R01 studies in African children utilizing mRNA-Seq to identify novel therapeutic targets (PI: Perkins). State-of-the-art methodologies and modeling efforts in place in our laboratories will be applied to create solutions for improving outcomes in COVID-19 patients. This will be achieved by following non-severe and severe COVID-19 patients across hospitalization from different ancestral groups to successfully complete three specific aims: 1) determine the impact of SARS-CoV-2 viral load dynamics on disease severity, 2) identify gene expression networks that mediate disease severity, and 3) identify prioritized FDA-approved compounds that modulate gene networks associated with enhanced disease severity for use in future clinical trials. In a short time, we have generated extensive data on viral load dynamics and identified novel gene networks with target-compound matches. We present data showing that individuals of AI/AN descent have significantly higher and protracted viral loads in peripheral blood and more severe disease, despite comparable co-morbid factors with other groups. The proposed investigations have direct translational impact, particularly in disproportionately affected ancestral groups by defining the host immune response to SARS-CoV-2, identifying biomarkers for risk assessment, prognosis, and disease progression, and fostering drug repurposing to reduce disease severity and mortality.