Big data and small molecules for Alzheimer's disease
阿尔茨海默病的大数据和小分子
基本信息
- 批准号:10168854
- 负责人:
- 金额:$ 41.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2019-nCoVAcute bronchitisAdmission activityAdult Respiratory Distress SyndromeAgeAge-YearsAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAlzheimer&aposs disease therapyAngiotensin IAngiotensin IIAngiotensin-Converting Enzyme InhibitorsAreaAssisted Living FacilitiesBig DataBindingBiologicalCLC GeneCOVID-19COVID-19 pandemicCellsCessation of lifeClinicalClinical ResearchCodeCommunitiesCountyDataData AnalysesData SetDatabasesDementiaDiagnosisDiseaseElderlyEnvironmentEnzyme Inhibitor DrugsExhibitsFDA approvedFundingGenderGeographic LocationsGoalsHealth care facilityHomologous GeneHospitalizationHumanHypertensionICD-9Impaired cognitionIndividualInfectionIntensive Care UnitsInternational Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10)Long-Term CareLower Respiratory Tract InfectionMechanical VentilatorsMusNeurodegenerative DisordersNursing HomesOnset of illnessOrganoidsOutcomePathologyPatientsPersonsPharmaceutical PreparationsPneumoniaPopulationPredispositionPrevalenceProteinsPublishingQuarantineRecombinantsReportingResearchRespiratory FailureRiskRisk FactorsSARS coronavirusSamplingServicesSeveritiesSymptomsTauopathiesTherapeuticTreatment EfficacyUnited States National Institutes of HealthVeteransViral Load resultWorkblood-brain barrier crossingcommunity livingcomorbiditydosageimprovedimproved outcomelow socioeconomic statusmetropolitanmortalityparent grantparent projectpre-clinicalsmall molecule
项目摘要
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
养老院社区超过一半的居民患有认知障碍
阿尔茨海默病(AD)或AD相关痴呆症(ADRD),以及美国新冠肺炎所有死亡病例中有三分之一是长期-
定期护理机构的居民。新冠肺炎大流行使AD患者面临更大的呼吸衰竭风险
和死亡率。在老年人中流行的高血压导致更严重的新冠肺炎
症状。这项补充NIH应用程序的目标是检查AD患者是否容易患上
感染严重急性呼吸综合征冠状病毒(SARS-CoV-2)可改善临床预后
新冠肺炎使用血管紧张素转换酶抑制剂(ACEI)。此补充申请适用于
我们由NIA资助的母公司项目的范围是“阿尔茨海默病的大数据和小分子(RF1-
AG063913)。来自父母项目的假设是直立性神经病和相关的神经退行性变
用血管紧张素转换酶抑制剂和他汀类药物治疗的小鼠的疾病病理可以被抑制。对此的假设是
补充项目是ACEI降低SARS的易感性、严重性和改善预后-
阿尔茨海默病患者冠状病毒2型感染的研究这项补充研究与母项目的目标相同,即
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)的迫切需要。
我们方法的科学前提是强有力的。首先,新冠肺炎和阿尔茨海默病患者血管紧张素II均升高
使血管紧张素转换酶(血管紧张素转换酶I至II)成为抑制的主要靶点。第二,SARS-CoV-2结合
通过血管紧张素转换酶同系物ACE2转移到靶细胞。第三,用重组血管紧张素转换酶2处理人细胞有机物
降低SARS-CoV-2病毒载量,ACEI治疗患者上调ACE2
高血压。使用国家数据库,我们报告了显著延长的临床前(无症状)
接受血管紧张素转换酶抑制剂和他汀类药物治疗的受试者与未服用任何药物的受试者相比,在AD发病前的间隔时间。我们
已在ACEI上确定了约350,000名受试者,有足够的权力确定是否存在
血管紧张素转换酶抑制物与新冠肺炎在AD患者中的相关性我们建议达到三个具体目标。
目的1.确定AD患者对SARS-CoV-2感染的易感性。这是一个独特的目标,是对
家长使用原始数据集扩展了新冠肺炎上的数据和其他变量,包括
地理区域。目的2.确定单个血管紧张素转换酶抑制剂与减少
新冠肺炎在药物治疗的AD患者中的应用我们会将所有十种处方的血管紧张素转换酶分为血脑屏障(BBB)
交叉和非交叉ACEI,并确定哪组/单个ACEI减少
新冠肺炎在AD患者中的应用目的3.确定血管紧张素转换酶抑制剂治疗与COVID严重程度的关系。
阿尔茨海默病患者有19种症状。新冠肺炎的严重程度将由自我隔离、住院、
重症监护病房入院、使用机械呼吸机以及死亡率。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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LEE E. GOLDSTEIN其他文献
LEE E. GOLDSTEIN的其他文献
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{{ truncateString('LEE E. GOLDSTEIN', 18)}}的其他基金
Impact of Toxic Metal Exposures in Novel Genetic Mouse Models of Late-Onset Alzheimer's Disease
有毒金属暴露对迟发性阿尔茨海默病的新型基因小鼠模型的影响
- 批准号:
10901030 - 财政年份:2023
- 资助金额:
$ 41.25万 - 项目类别:
Lasting Impacts: Dynamic, Fully Natural Bioprinted 3D Human Neurovascular Biomimetic Model to Study Traumatic Brain Injury Pathophysiology
持久影响:用于研究创伤性脑损伤病理生理学的动态、完全自然的生物打印 3D 人体神经血管仿生模型
- 批准号:
10318506 - 财政年份:2021
- 资助金额:
$ 41.25万 - 项目类别:
Lens β-Amyloid Biomarker for Early Detection of Preclinical Alzheimer's Disease in the Framingham Study
Framingham 研究中用于早期检测临床前阿尔茨海默病的晶状体 β-淀粉样蛋白生物标志物
- 批准号:
10214179 - 财政年份:2021
- 资助金额:
$ 41.25万 - 项目类别:
Lasting Impacts: Dynamic, Fully Natural Bioprinted 3D Human Neurovascular Biomimetic Model to Study Traumatic Brain Injury Pathophysiology
持久影响:用于研究创伤性脑损伤病理生理学的动态、完全自然的生物打印 3D 人体神经血管仿生模型
- 批准号:
10916751 - 财政年份:2021
- 资助金额:
$ 41.25万 - 项目类别:
TBI identification and monitoring through retinal scanning
通过视网膜扫描进行 TBI 识别和监测
- 批准号:
10383172 - 财政年份:2020
- 资助金额:
$ 41.25万 - 项目类别:
TBI Identification and Monitoring Through Retinal Scanning
通过视网膜扫描识别和监测 TBI
- 批准号:
10593933 - 财政年份:2020
- 资助金额:
$ 41.25万 - 项目类别:
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:
10217833 - 财政年份:2019
- 资助金额:
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