Innate immunity in Alzheimer's disease: Role of toll-like receptor signaling
阿尔茨海默氏病的先天免疫:Toll 样受体信号传导的作用
基本信息
- 批准号:7904117
- 负责人:
- 金额:$ 31.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2014-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acute-Phase ProteinsAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAmyloid ProteinsAmyloidosisAnimal ModelAnimalsBehavioralBrainCellsCerebrumComplementConflict (Psychology)DementiaDependovirusDepositionDiseaseDisease ProgressionElderlyEtiologyEventFunctional disorderGene DeliveryGeneticGoalsImmuneImmune responseImmune systemIn VitroInflammationIngestionInterleukin-10Interleukin-17Interleukin-6LigandsLipopolysaccharidesMediatingMicrogliaModalityMolecular ProfilingMouse Cell LineMouse StrainsMusMutationMyelogenousNamesNatural ImmunityNerve DegenerationNeuraxisPartner in relationshipPathologyPathway interactionsPatientsPattern recognition receptorPeptide HydrolasesPhagocytesPlayProteinsReceptor SignalingRecombinant adeno-associated virus (rAAV)ResearchRoleSenile PlaquesSignal TransductionSignaling MoleculeStagingTLR4 geneTestingTissue SampleTissuesToll-like receptor 6Toll-like receptorsTransgenic MiceUp-Regulationcerebrovascularchemokinecognitive functioncongeniccytokinecytotoxicgene therapyimprovedin vivolipoteichoic acidmouse modelmutantnoveloverexpressionpathogenpreventpublic health relevancereceptorresponsewasting
项目摘要
DESCRIPTION (provided by applicant): Patients with Alzheimer's disease (AD) develop deposits of aggregated amyloid ¿-protein (A¿) in the brain. A¿ accumulation is thought to be a causal event in the etiology of AD. Fibrillar A2 deposits in AD brain are accompanied by innate immune responses such as activated microglia and increased levels of cytokines. Accumulating evidence supports the hypothesis that activated microglia, innate immune cells in the central nervous system, play a pivotal role in the AD progression: either clearing A¿ deposits by phagocytic activity or releasing cytotoxic substances. Toll-like receptors (TLRs) are a class of pattern-recognition receptors in the innate immune system. One of the important roles of TLRs is to activate phagocytes/microglia to respond to insults including pathogens and damaged host cells, leading to clearance of pathogens, damaged tissues and accumulated wastes. We hypothesize that these protective functions are mediated by MyD88-dependent pathways and that A¿ load in the brain can be modulated by TLR4 signaling. We will determine the roles of MyD88-dependent pathways and TLR4 signaling in A¿ clearance by completing the Specific Aim 1 and 2. We further hypothesize that A¿ load in the brain and cognitive functions are modulated by TLR4 effector cytokines/chemokines, which will be tested by performing Aim 3. In Aim 4, we will test the hypothesis that accumulation of A¿ in the brain induces dysfunction of TLR4 signaling in microglia resulting in exacerbation of A¿ deposition in AD patients and AD mouse models. Specific Aims are (Aim 1) to determine cerebral A¿ load, inflammation and behavioral deficits in AD mouse models on a MyD88-deficient genetic background, (Aim 2) to determine cerebral A¿ load, inflammation and behavioral deficits in AD mouse models that overexpress TLR4, (Aim 3a) to compare cerebral cytokine and chemokine expression profiles between TLR4 wild-type and mutant AD mouse models, (Aim 3b) to overexpress TLR4 effector cytokines and/or chemokines in the brain via adeno-associated virus gene delivery and determine cerebral A¿ load, inflammation and behavioral deficits in the AD mouse models, and (Aim 4) to determine whether A¿ induces dysfunction of TLR signaling, using cultured microglia, AD mouse models and tissue samples from AD patients. The long term goal of this research is to determine the roles of TLR signaling and its effector cytokines/chemokines in the AD progression. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. Patients with AD develop deposits of aggregated amyloid 2 protein (A¿) in the brain. A¿ accumulation is thought to be a causal event in the etiology of AD. This study will elucidate the mechanisms by which A¿ deposits are cleared and serve as a proof of principle to demonstrate if our novel cytokine/chemokine gene therapy modality is effective in treating an animal model of AD.
描述(申请人提供):阿尔茨海默病(AD)患者在大脑中形成聚集的淀粉样蛋白(A?)沉积。在阿尔茨海默病的病因中,积聚被认为是一种因果事件。阿尔茨海默病脑内纤维状A2沉积伴随着先天免疫反应,如激活的小胶质细胞和升高的细胞因子水平。越来越多的证据支持这样的假设,即激活的小胶质细胞,即中枢神经系统中的先天免疫细胞,在AD的进展中发挥关键作用:要么通过吞噬活动清除沉积的A?,要么释放细胞毒性物质。Toll样受体是天然免疫系统中的一类模式识别受体。TLRs的重要作用之一是激活吞噬细胞/小胶质细胞对包括病原体和受损宿主细胞在内的伤害做出反应,从而清除病原体、受损组织和堆积的废物。我们假设这些保护功能是由MyD88依赖的通路介导的,大脑中的A?负荷可以通过TLR4信号来调节。我们将通过完成特定的目标1和2来确定MyD88依赖的通路和TLR4信号在A?清除中的作用。我们进一步假设A?在大脑中的负荷和认知功能受到TLR4效应细胞因子/趋化因子的调节,这将通过执行目标3来验证。在目标4中,我们将检验A?在大脑中的积累导致小胶质细胞中TLR4信号的功能障碍,从而加剧AD患者和AD小鼠模型中A?的沉积。具体目标是(目标1)确定MyD88缺乏遗传背景的AD小鼠模型的脑A负荷、炎症和行为缺陷,(目标2)确定过度表达TLR4的AD小鼠模型的脑A负荷、炎症和行为缺陷,(目标3a)比较TLR4野生型和突变型AD小鼠模型的脑细胞因子和趋化因子表达谱,(目标3b)通过腺相关病毒基因传递在脑内过表达TLR4效应细胞因子和/或趋化因子,并确定AD模型中的脑A负荷、炎症和行为缺陷,以及(目的4)利用培养的小胶质细胞、AD小鼠模型和AD患者的组织样本,确定A是否导致TLR信号转导功能障碍。本研究的长期目标是确定TLR信号及其效应细胞因子/趋化因子在AD进展中的作用。公共卫生相关性:阿尔茨海默病(AD)是导致老年人痴呆症的最常见原因。然而,到目前为止,还没有令人满意的治疗AD的方法。阿尔茨海默病患者会在大脑中形成聚集的淀粉样蛋白2(A?)。在阿尔茨海默病的病因中,积聚被认为是一种因果事件。这项研究将阐明A?沉积被清除的机制,并作为原则证明,证明我们新的细胞因子/趋化因子基因治疗方式在治疗AD动物模型中是否有效。
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 }}
Ken-ichiro Fukuchi其他文献
Ken-ichiro Fukuchi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 }}
{{ truncateString('Ken-ichiro Fukuchi', 18)}}的其他基金
Role of MyD88 signaling in systemic inflammation and Alzheimer disease
MyD88 信号在全身炎症和阿尔茨海默病中的作用
- 批准号:
10456872 - 财政年份:2021
- 资助金额:
$ 31.86万 - 项目类别:
Role of MyD88 signaling in systemic inflammation and Alzheimer disease
MyD88 信号在全身炎症和阿尔茨海默病中的作用
- 批准号:
10314883 - 财政年份:2021
- 资助金额:
$ 31.86万 - 项目类别:
Role of MyD88 signaling in systemic inflammation and Alzheimer disease
MyD88 信号在全身炎症和阿尔茨海默病中的作用
- 批准号:
10611489 - 财政年份:2021
- 资助金额:
$ 31.86万 - 项目类别:
Altering immune tolerance in Alzheimer disease
改变阿尔茨海默病的免疫耐受性
- 批准号:
9979733 - 财政年份:2019
- 资助金额:
$ 31.86万 - 项目类别:
Role of extracellular vesicles in the high-fat diet-induced risk of Alzheimer disease
细胞外囊泡在高脂肪饮食诱发的阿尔茨海默病风险中的作用
- 批准号:
9385535 - 财政年份:2017
- 资助金额:
$ 31.86万 - 项目类别:
Role of diet-induced miR-34a in Alzheimer disease and dementia
饮食诱导的 miR-34a 在阿尔茨海默病和痴呆中的作用
- 批准号:
9225329 - 财政年份:2017
- 资助金额:
$ 31.86万 - 项目类别:
Role of the MyD88-independent pathway in Alzheimers disease
MyD88 独立通路在阿尔茨海默病中的作用
- 批准号:
8511261 - 财政年份:2013
- 资助金额:
$ 31.86万 - 项目类别:
Role of the MyD88-independent pathway in Alzheimers disease
MyD88 独立通路在阿尔茨海默病中的作用
- 批准号:
8676620 - 财政年份:2013
- 资助金额:
$ 31.86万 - 项目类别:
Catalytic and non-catalytic Ig gene delivery for Alzheimer's disease
阿尔茨海默病的催化和非催化 Ig 基因递送
- 批准号:
7963696 - 财政年份:2010
- 资助金额:
$ 31.86万 - 项目类别:
Catalytic and non-catalytic Ig gene delivery for Alzheimer's disease
阿尔茨海默病的催化和非催化 Ig 基因递送
- 批准号:
8081811 - 财政年份:2010
- 资助金额:
$ 31.86万 - 项目类别:
相似海外基金
Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
- 批准号:
502556 - 财政年份:2024
- 资助金额:
$ 31.86万 - 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
- 批准号:
10659303 - 财政年份:2023
- 资助金额:
$ 31.86万 - 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
- 批准号:
10674405 - 财政年份:2023
- 资助金额:
$ 31.86万 - 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
- 批准号:
10758772 - 财政年份:2023
- 资助金额:
$ 31.86万 - 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
- 批准号:
10676499 - 财政年份:2023
- 资助金额:
$ 31.86万 - 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
- 批准号:
2748611 - 财政年份:2022
- 资助金额:
$ 31.86万 - 项目类别:
Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
- 批准号:
22K05630 - 财政年份:2022
- 资助金额:
$ 31.86万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
- 批准号:
10532032 - 财政年份:2022
- 资助金额:
$ 31.86万 - 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
- 批准号:
10525070 - 财政年份:2022
- 资助金额:
$ 31.86万 - 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
- 批准号:
10689017 - 财政年份:2022
- 资助金额:
$ 31.86万 - 项目类别: