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

来自不同受影响祖先群体的住院 COVID-19 患者的时间转录组学用于治疗发现

• 批准号: 10442561
• 负责人: Douglas Jay Perkins
• 金额: $ 75.46万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442561
• 关键词: 2019-nCoV; Academic Medical Centers; Address; Affect; African; African American population; Age; Alaska Native; American Indians; Biological Markers; Blood specimen; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; COVID-19 treatment; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Communicable Diseases; Country; Data; Development; Disease; Disease Progression; Enrollment; Equilibrium; FDA approved; Fostering; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genomic approach; Hispanic Americans; Hispanic Populations; Hispanic ancestry; Hispanic-serving Institution; Hospitalization; Hospitals; Human; Immune Response Genes; Immune response; Immunoassay; Immunotherapy; Individual; Inflammatory; Institutional Review Boards; Investigation; Knowledge; Laboratories; Life; Mediating; Methodology; Methods; Minority Groups; Modeling; Molecular; Monitor; Morbidity - disease rate; Navajo; New Mexico; Outcome; Outcome Study; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Play; Population; Population Sizes; Positioning Attribute; Prognosis; Research Personnel; Risk Assessment; Role; Severity of illness; Therapeutic; Time; Universities; Upper respiratory tract; Vaccines; Viral; Viral Load result; World Health Organization; biomedical referral center; comorbidity; drug repurposing; experience; gene network; global health; hospitalization rates; improved; improved outcome; mRNA sequencing; mortality; multidisciplinary; new therapeutic target; novel; novel coronavirus; novel therapeutics; pandemic disease; patient population; peripheral blood; recruit; response; severe COVID-19; small molecule; tertiary care; transcriptomics; translational impact; trauma centers; tribal lands

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.

项目概要 SARS-CoV-2 是一种新型冠状病毒，可导致 COVID-19，这种疾病已感染超过 4600 万人 截至 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 最近全国范围内的每日病例数和住院率均创纪录。这已经特别 新墨西哥州（NM）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，某些 少数群体，即非裔美国人、西班牙裔和美洲印第安人/阿拉斯加原住民 (AI/AN) 遭受苦难 与 COVID-19 的比例不成比例。新墨西哥州拥有最高比例的西班牙裔血统，也是最大的西班牙裔血统之一 AI/AN 人群，这两组分别占累计病例的 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，高出 7.9 倍 住院率和年龄调整死亡率高出 10.6 倍。作为唯一的学术医疗中心和 该州一级创伤中心，新墨西哥大学医院 (UNMH) 发挥了主要作用 照顾 COVID-19 患者。 UNMH 是新墨西哥州及周边地区的主要三​​级护理转诊中心 地区，包括纳瓦霍族和其他部落土地。因此，我们具有独特的优势来解决 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 在受影响不成比例的祖先群体中。 2 月中旬，新墨西哥大学全球健康中心组建了一个 多学科研究小组致力于应对 COVID-19 的挑战。截至 10 月 31 日，我们已 招募并跟踪了 167 名住院的 COVID-19 患者，为快速转化提供了机会 计划的三年研究中的影响。该实验策略与我们正在进行的 R01 研究类似 非洲儿童利用 mRNA-Seq 来识别新的治疗靶点（PI：Perkins）。最先进的 我们实验室现有的方法和建模工​​作将用于创建改进的解决方案 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 来自不同祖先群体的住院治疗成功完成三个具体目标：1) 确定 SARS-CoV-2 病毒载量动态对疾病严重程度的影响，2) 确定基因表达网络 介导疾病严重程度，3) 确定 FDA 批准的调节基因网络的优先化合物 与未来临床试验中使用的疾病严重程度增强相关。在很短的时间内，我们就生成了 有关病毒载量动态的大量数据，并确定了具有目标化合物匹配的新型基因网络。我们 目前的数据显示，AI/AN 血统的个体在 尽管共病因素与其他群体相当，但外周血和更严重的疾病。这 拟议的调查具有直接的转化影响，特别是在受影响不成比例的祖先 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，并促进药物再利用以降低疾病严重程度和死亡率。