Identifying the mechanistic role of and reversing aberrant neural activity in Alzheimer's Disease
识别阿尔茨海默病中异常神经活动的机制作用并逆转
基本信息
- 批准号:10740789
- 负责人:
- 金额:$ 12.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease therapyAmyloid beta-ProteinAnatomyAntibodiesBrainBrain regionCellsClinicalCognitionCognitiveCognitive deficitsCompensationDataDevelopmentDiseaseDisease ProgressionExhibitsFacultyHeadHumanImageImpaired cognitionIntelligenceLabelLearningLightLinkLongitudinal StudiesMapsMedicalMemoryMentorsMicroscopyModelingMusNeuronsNeurosciencesPathologyPatientsPatternPhasePlayPositioning AttributePreparationProtocols documentationResearch PersonnelResolutionRoleStainsSymptomsSystemTechniquesTechnologyTestingTherapeuticTimeTissuesTrainingUniversitiesVirusWorkcareer developmentclinically relevantcognitive performancecognitive taskdesigndiagnostic strategyearly detection biomarkersexperimental studyhuman imagingimaging modalityimprovedmouse modelneuralneural stimulationoptogeneticsprospectiveprotein aggregationrecruitskillstau Proteinstau aggregationtemporal measurementtherapeutic targettwo-photon
项目摘要
Project Summary/Abstract
Alzheimer’s Disease (AD) is a devastating disease with enormous unmet medical need. It is likely necessary to
understand, detect, and treat Alzheimer’s Disease earlier in disease development. Patients often exhibit aberrant
neural activity even before pathology or cognitive decline. Amyloid-beta (Ab) and tau can perturb neural activity,
and activity can affect their levels, thus aberrant neural activity may be both a symptom and cause of Ab and
tau, forming a vicious cycle. This project will investigate the hypothesis that aberrant neural activity is a primary
driver of and tractable therapeutic target for Alzheimer’s Disease, and that targeting it can rescue cognitive
deficits. There is a lack of direct evidence on the causative role of aberrant neural activity in Alzheimer’s Disease,
let alone the mechanisms, a significant gap in our understanding. Human imaging methods have low resolution,
and human studies cannot use precise perturbations to test direct cause and effect. Yet, stimulation therapies
are used on patients, using limited data to inform protocols, resulting in promising but inconclusive results.
This
project will use cutting-edge systems neuroscience techniques to conduct single-cell resolution examination and
perturbation of the brain to determine the mechanistic role of aberrant neural activity in cognitive decline in
Alzheimer’s Disease mice, and to reverse it. To identify aberrant single-neuron and network dynamics, 2-photon
Ca2+ imaging will be used in Alzheimer’s Disease mice during cognitive tasks over disease progression. This will
be the first longitudinal study of single-neuron activity in Alzheimer’s Disease mice during cognitive tasks, and
the first lifelong study of neural activity. To discover activity-based anatomical connectivity changes, activity-
dependent neuron projection labeling will be used to label neurons activated during learning and recall. Tissue-
clearing will enable imaging of projections across the entire brain in 3D, along with Ab and tau, over disease
progression. This will discover specific brain regions, circuits, and cells that change in parallel to Ab and tau and
correlate with cognition. These will be the first brain-wide, activity-dependent projection tracing experiments, and
the first longitudinal study of anatomical connectivity changes in Alzheimer’s Disease. To test the functional role
of aberrant activity and to restore cognition, single-cell optogenetics will be used to recapitulate or reverse the
activity patterns changed in Alzheimer’s Disease, and circuits will be modulated to correct connectivity.
Optogenetics will be used in AD mice to determine if AD therapies improve cognition through effects on neural
activity. The investigator will receive technical, conceptual, and career development training from a mentoring
team of leading experts in world-class labs at Stanford University in preparation for transition to a faculty position.
This work will discover fundamental mechanisms of Alzheimer’s Disease. It will result in unprecedented, high-
resolution, comprehensive data on changes in neural activity and connectivity during Alzheimer’s Disease that
will identify the specific circuits, cells, and activity dynamics that drive cognitive decline, which will help inform
intelligent design of new, precise, and earlier biomarkers, diagnostic strategies, and therapeutic treatments.
项目摘要/摘要
阿尔茨海默病(AD)是一种毁灭性的疾病,有着巨大的未得到满足的医疗需求。很可能有必要
在疾病发展的早期了解、检测和治疗阿尔茨海默病。患者经常表现出异常
神经活动甚至在病理或认知功能衰退之前。淀粉样β蛋白(Ab)和tau可以扰乱神经活动,
而活动可以影响它们的水平,因此异常的神经活动可能是AB和AND的症状和原因
牛磺酸,形成恶性循环。这个项目将调查这样的假设,即异常的神经活动是
阿尔茨海默病的驱动力和易处理的治疗靶点,以及靶向它可以挽救认知
赤字。关于阿尔茨海默病中异常神经活动的致病作用,缺乏直接证据。
更不用说机制了,这是我们理解中的一个重大差距。人类的成像方法分辨率较低,
人类研究不能使用精确的扰动来测试直接的因果关系。然而,刺激疗法
在患者身上使用,使用有限的数据来告知方案,导致有希望但不确定的结果。
这
该项目将使用尖端系统神经科学技术进行单细胞分辨率检查和
大脑的扰动以确定异常神经活动在认知能力下降中的机制作用
阿尔茨海默病小鼠,并逆转它。为了识别异常的单个神经元和网络动力学,双光子
钙离子成像将用于阿尔茨海默病小鼠在疾病进展的认知任务中。这将是
首次对阿尔茨海默病小鼠在认知任务中的单个神经元活动进行纵向研究,以及
第一个终生研究神经活动的人。为了发现基于活动的解剖连接变化,活动-
依赖神经元投射标记将用于标记在学习和回忆过程中激活的神经元。组织-
清除后,将能够在疾病上对整个大脑以及抗体和tau进行3D投影成像
进步。这将发现与Ab和tau平行变化的特定大脑区域、回路和细胞,以及
与认知相关。这将是第一个全脑范围的、依赖活动的投影追踪实验,以及
首次对阿尔茨海默病的解剖连接变化进行纵向研究。测试功能角色
为了恢复认知,单细胞光遗传学将被用来概括或逆转
阿尔茨海默病的活动模式发生了变化,电路将被调制以纠正连接。
将在AD小鼠中使用光遗传学来确定AD治疗是否通过对神经的影响来改善认知
活动。调查员将从指导人员那里接受技术、概念和职业发展培训
斯坦福大学世界级实验室的领先专家团队,为过渡到教员职位做准备。
这项工作将发现阿尔茨海默病的基本机制。它将导致史无前例的,高度的-
解决方案,关于阿尔茨海默病期间神经活动和连接性变化的全面数据
将确定驱动认知能力下降的特定电路、细胞和活动动力学,这将有助于
智能设计新的、精确的和更早的生物标志物、诊断策略和治疗方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Theodore Terence Ho其他文献
Theodore Terence Ho的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 12.83万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 12.83万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 12.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 12.83万 - 项目类别:
Studentship