Big data and small molecules for Alzheimer's disease

阿尔茨海默病的大数据和小分子

• 批准号: 10168854
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10168854
• 关键词: 2019-nCoV; Acute bronchitis; Admission activity; Adult Respiratory Distress Syndrome; Age; Age-Years; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Area; Assisted Living Facilities; Big Data; Binding; Biological; CLC Gene; COVID-19; COVID-19 pandemic; Cells; Cessation of life; Clinical; Clinical Research; Code; Communities; County; Data; Data Analyses; Data Set; Databases; Dementia; Diagnosis; Disease; Elderly; Environment; Enzyme Inhibitor Drugs; Exhibits; FDA approved; Funding; Gender; Geographic Locations; Goals; Health care facility; Homologous Gene; Hospitalization; Human; Hypertension; ICD-9; Impaired cognition; Individual; Infection; Intensive Care Units; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10); Long-Term Care; Lower Respiratory Tract Infection; Mechanical Ventilators; Mus; Neurodegenerative Disorders; Nursing Homes; Onset of illness; Organoids; Outcome; Pathology; Patients; Persons; Pharmaceutical Preparations; Pneumonia; Population; Predisposition; Prevalence; Proteins; Publishing; Quarantine; Recombinants; Reporting; Research; Respiratory Failure; Risk; Risk Factors; SARS coronavirus; Sampling; Services; Severities; Symptoms; Tauopathies; Therapeutic; Treatment Efficacy; United States National Institutes of Health; Veterans; Viral Load result; Work; blood-brain barrier crossing; community living; comorbidity; dosage; improved; improved outcome; low socioeconomic status; metropolitan; mortality; parent grant; parent project; pre-clinical; small molecule

ABSTRACT More than half of residents in nursing home communities suffer from cognitive impairment with Alzheimer’s disease (AD) or AD related dementia (ADRD), and one-third of all US COVID-19 deaths are long- term care facility residents. The COVID-19 pandemic places AD patients at a greater risk of respiratory failure and mortality. Hypertension, which is prevalent among elderly populations, results in more severe COVID-19 symptoms. The goal of this supplement NIH application is to examine whether AD patients vulnerable to infection by severe acute respiratory syndrome coronavirus (SARS-CoV-2) can improve clinical outcomes of COVID-19 with angiotensin converting enzyme inhibitors (ACEI). This supplement application fits within the scope of our NIA-funded parent project, “Big data and small molecules for Alzheimer’s disease (RF1- AG063913).” The hypothesis from the parent project was that tauopathy and related neurodegenerative disease pathologies can be suppressed in mice treated with ACEI and statins. The hypothesis for this supplement project is that ACEI reduces the susceptibility, severity, and improves outcomes of SARS- CoV-2 infection in AD patients. This supplement research shares the same goal of the parent project, which aims to meet an urgent need to identify and fast-track new AD therapies (ACEI) with a clear efficacy readout. The scientific premise for our approach is strong. First, angiotensin II is elevated in both COVID-19 and AD patients, making ACE (converting angiotensin I to II) the prime target for inhibition. Second, SARS-CoV-2 binds to its target cells through ACE homolog ACE2. Third, treating human cell organoids with recombinant ACE2 reduces the viral load of SARS-CoV-2, and treating patients with ACEI up-regulates ACE2 in those with hypertension. Using a national database, we have reported significantly longer preclinical (asymptomatic) intervals before AD onset in subjects treated with ACEI and statins compared to those taking neither drug. We have identified ~350,000 subjects on an ACEI, with sufficient power to determine whether there is an association between ACEI and COVID-19 among AD patients. We propose to achieve three Specific Aims. Aim 1. To determine the susceptibility of AD to SARS-CoV-2 infection. This is a unique Aim that supplements the parent grant by using the original data set extended with data on COVID-19 and other variables including geographic regions. Aim 2. To determine the association of individual ACEI with the reduced occurrence of COVID-19 in medicated AD patients. We will divide all ten prescribed ACEIs into blood-brain barrier (BBB) crossing and non-crossing ACEIs and determine which group of/individual ACEIs reduce the occurrence of COVID-19 in AD patients. Aim 3. To determine the association of ACEI therapies with the severity of COVID- 19 symptoms in AD patients. The severity of COVID-19 will be defined by self-quarantine, hospitalization, intensive care unit admission, use of mechanical ventilators, as well as mortality.

摘要 超过一半的养老院社区居民患有认知障碍， 阿尔茨海默病（AD）或AD相关痴呆症（ADRD），以及三分之一的美国COVID-19死亡是长期的- 长期护理机构的居民。COVID-19大流行使AD患者面临更大的呼吸衰竭风险 and mortality.老年人群中普遍存在的高血压会导致更严重的COVID-19 症状这项补充NIH申请的目的是检查AD患者是否容易受到 严重急性呼吸综合征冠状病毒（SARS-CoV-2）感染可改善 COVID-19与血管紧张素转换酶抑制剂（ACEI）。此补充应用程序适用于 我们由NIA资助的母项目“阿尔茨海默病的大数据和小分子（RF 1-）”的范围 AG063913）”。母项目的假设是tau蛋白病和相关的神经退行性疾病 在用ACEI和他汀类药物治疗的小鼠中可以抑制疾病病理。对此的假设是 补充项目是ACEI降低SARS的易感性、严重程度和改善预后- AD患者中的CoV-2感染。这项补充研究与母项目的目标相同， 旨在满足识别和快速跟踪具有明确疗效读数的新AD疗法（ACEI）的迫切需求。 我们的方法的科学前提是强有力的。首先，血管紧张素II在COVID-19和AD中均升高 患者，使ACE（将血管紧张素I转化为II）成为抑制的主要靶点。其次，SARS-CoV-2结合 通过ACE同系物ACE 2将其导入靶细胞。第三，用重组ACE 2处理人细胞类器官 降低SARS-CoV-2的病毒载量，ACEI治疗患者可上调 高血压使用国家数据库，我们报告了临床前（无症状） 与未服用任何药物的受试者相比，接受ACEI和他汀类药物治疗的受试者在AD发作前的时间间隔。我们 已经确定了约350，000例接受ACEI治疗的受试者，有足够的能力确定是否存在 AD患者中ACEI与COVID-19的相关性。我们提出了三个具体目标。 目标1.确定AD对SARS-CoV-2感染的易感性。这是一个独特的目的，补充 通过使用原始数据集扩展了COVID-19数据和其他变量，包括 地理区域。目标2.为了确定个体ACEI与降低血管紧张素转换酶抑制剂的发生率之间的关系， 接受药物治疗的AD患者中的COVID-19。我们将所有10种规定的ACEI分为血脑屏障（BBB） 交叉和非交叉ACEI，并确定哪组/个体ACEI可减少 AD患者中的COVID-19。目标3.为了确定ACEI治疗与COVID严重程度的相关性， AD患者的19个症状。COVID-19的严重程度将由自我隔离、住院治疗、 重症监护室入院、机械呼吸机的使用以及死亡率。