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.

抽象的 超过一半的疗养院社区居民患有认知障碍 阿尔茨海默氏病（AD）或AD相关痴呆症（ADRD），以及所有美国covid-19的死亡人数中有三分之一是长期的 术语护理设施的居民。 和死亡率。 症状。 严重急性呼吸综合征冠状病毒（SARS-COV-2）感染可以改善 与血管紧张素转化酶抑制剂（ACEI）的共vid-19。 我们NIA资助的家长项目的范围，“阿尔茨海默氏病的大数据和小分子（RF1- AG063913）。 用ACEI和他汀类药物治疗的小鼠可以抑制疾病。 补充项目是，ACEI降低了敏感性，严重性，并改善了SARS- AD患者的COV-2感染。 旨在满足迫切需要识别和快速轨道新的广告疗法（ACEI），并具有清晰的功效读数。 我们的方法的科学前提是首先，血管紧张素II II均在19和AD中升高 患者，使ACE（将血管紧张素I转化为II）是遗传的主要目标 TOS靶细胞通过ACE同源物ACE2。 减少SARS-COV-2的病毒载荷，并用ACEI治疗Patiation在患有ACE2的患者中 高血压。使用国家数据库，我们报告了更长的临床前 与未服用我们的药物相比，用ACEI和他汀类药物治疗的受试者的AD发作之前的间隔 在ACEI上确定了约35万受试者，并具有足够的能力来确定有一个 ACEI和COVID-19之间的关联我们提议达到三个特定的AM。 目标1。确定AD对SARS-COV-2感染的敏感性。 父母赠款通过使用COVID-19和其他可变性的数据进行扩展的原始数据集，包括 地理区域。 COVID-19中的AD患者。 越过和非交叉的acecis，并确定哪个/单个ACEIS降低了发生的情况 AD患者的COVID-19。 AD患者的19症状。 重症监护病房的入院，使用机械呼吸机以及死亡率。