The developmental effects of sex chromosomes and hormones specify microglial inflammation in Alzheimer's diseaes
性染色体和激素的发育影响明确了阿尔茨海默病中的小胶质细胞炎症
基本信息
- 批准号:10553269
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloidBiochemicalBiological FactorsBiologyBrainBreedingCell Differentiation processCellsComplementDementiaDepositionDevelopmentDevelopmental ProcessDiseaseDisease OutcomeDisease ProgressionDisparityEstradiolFeminizationFour Core GenotypesGene ExpressionGeneticGerm CellsGoalsGonadal HormonesGonadal Steroid HormonesHealthHormonalHormonesImmuneIncidenceIndomethacinInflammationInflammatoryInflammatory ResponseKnowledgeLongevityMasculineMeasuresMediatingMediatorMethodologyMethodsMicrogliaMissionModelingMolecularMorphologyMusNeonatalNerve DegenerationNeuroanatomyNeurodegenerative DisordersNeurofibrillary TanglesNeuronsNuclear ReceptorsOnset of illnessOutcomePTPRC genePlayPrevalencePreventionPrevention strategyProbabilityProcessProteinsPublic HealthResearchRoleSeverity of illnessSex ChromosomesSex DifferencesSignal TransductionSpecific qualifier valueTechniquesTestingUnited States National Institutes of HealthWomanage relatedbrain cellcombatextracellularglial activationimmune activationinflammatory milieuinnovationinsightmouse modelneurochemistryneurofilamentneuroinflammationnovelnovel therapeutic interventionreceptor functionreduce symptomssexsexual dimorphismsuccesstherapeutically effectivetherapy developmenttreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
Although women are known to be disproportionally affected by Alzheimer’s disease (AD), the
underlying biology for this difference is unresolved. Our long-term goal is to help develop therapies that can be
used in the prevention and treatment of Alzheimer’s disease and other dementias where inflammation plays a
critical role. The overall objectives in this application are to (i) define the mechanisms that specify the
inflammatory response in the AD brain, and (ii) elucidate whether these are altered in the presence of
circulating hormones. Our central hypothesis is that sex differences in the brain’s immune cells are driven by
sex chromosomes and gonadal steroid hormones, resulting in divergent inflammatory processes and therefore
AD onset and progression. The rationale for this project is that determining how genetic and hormonal
mediators contribute to sex differences in the neuroinflammatory processes in AD will provide a strong
scientific framework whereby new therapeutic strategies can be developed. The central hypothesis will be
tested by pursuing two specific aims: 1) Determine the contribution of sex chromosomes to the inflammatory
environment of the AD brain; and 2) Determine the organizational effects of sex hormones in establishing the
inflammatory response in the AD brain. Under the first aim, the 5xFAD mouse model of AD will be combined
with the Four Core Genotype (FCG) mouse to separate chromosomal and gonadal sex in the context of AD.
Inflammation will be assessed using biochemical and molecular techniques to examine immune cell activation
and neuronal health and survival. For the second aim, the brains of 5xFAD mice will be masculinized or
feminized neonatally to ascertain the effects of gonadal hormones on inflammatory processes. The innovation
of this project lies in: 1) the aspects of sex not previously considered in AD models, 2) the contribution of cell
differentiation during development to AD risk in ways not previously considered, and 3) the use of
methodologies to shift the disease paradigm away from protein functional differences towards expression
differences. Providing critical insights to the mechanisms giving rise to immune dysregulation and
neuroinflammation in AD are significant because they have the potential to become the basis for new
therapeutic strategies.
项目总结/摘要
尽管已知女性会受到阿尔茨海默病(AD)的影响,
这种差异的潜在生物学尚未解决。我们的长期目标是帮助开发可以
用于预防和治疗阿尔茨海默病和其他痴呆症,其中炎症起作用,
关键作用。本申请中的总体目标是(i)定义指定
AD脑中的炎症反应,和(ii)阐明这些是否在存在下改变
循环荷尔蒙我们的中心假设是,大脑免疫细胞的性别差异是由
性染色体和性腺类固醇激素,导致不同的炎症过程,
AD发作和进展。这个项目的基本原理是,确定遗传和激素
介质有助于在AD的神经炎症过程中的性别差异,
科学框架,从而可以开发新的治疗策略。核心假设是
通过追求两个特定目标进行测试:1)确定性染色体对炎症的贡献,
AD大脑的环境;和2)确定性激素在建立AD大脑中的组织效应。
AD脑中的炎症反应。在第一个目标下,将AD的5xFAD小鼠模型与
用四核心基因型(FCG)小鼠在AD的背景下分离染色体和性腺性别。
炎症将使用生物化学和分子技术进行评估,以检查免疫细胞活化
神经元的健康和存活。对于第二个目的,将5xFAD小鼠的大脑雄性化或
雌性化以确定性腺激素对炎症过程的影响。创新
该项目的主要目的在于:1)以前在AD模型中未考虑的性别方面,2)细胞的贡献
在发展过程中的差异,以以前没有考虑的方式AD风险,和3)使用
将疾病模式从蛋白质功能差异转向表达差异的方法
差异为引起免疫失调的机制提供重要见解,
神经炎症在AD中是重要的,因为它们有可能成为新的基础。
治疗策略
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 }}
ERIN G REED其他文献
ERIN G REED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('ERIN G REED', 18)}}的其他基金
The developmental effects of sex chromosomes and hormones specify microglial inflammation in Alzheimer's diseaes
性染色体和激素的发育影响明确了阿尔茨海默病中的小胶质细胞炎症
- 批准号:
10370098 - 财政年份:2022
- 资助金额:
$ 39万 - 项目类别:
Merkel cells specify innervating SAI sensory neuron phenotype.
默克尔细胞指定支配 SAI 感觉神经元的表型。
- 批准号:
8608608 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
Merkel cells specify innervating SAI sensory neuron phenotype.
默克尔细胞指定支配 SAI 感觉神经元的表型。
- 批准号:
8452422 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
Merkel cells specify innervating SAI sensory neuron phenotype.
默克尔细胞指定支配 SAI 感觉神经元的表型。
- 批准号:
8315102 - 财政年份:2012
- 资助金额:
$ 39万 - 项目类别:
CD14 and TLRs in Abeta-Induced Microglial Signaling
Abeta 诱导的小胶质细胞信号转导中的 CD14 和 TLR
- 批准号:
7477636 - 财政年份:2007
- 资助金额:
$ 39万 - 项目类别:
CD14 and TLRs in Abeta-Induced Microglial Signaling
Abeta 诱导的小胶质细胞信号转导中的 CD14 和 TLR
- 批准号:
7329038 - 财政年份:2007
- 资助金额:
$ 39万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
- 批准号:
2601817 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
- 批准号:
2029039 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
- 批准号:
9888417 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
- 批准号:
17K11318 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
- 批准号:
BB/M50306X/1 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
- 批准号:
288272 - 财政年份:2013
- 资助金额:
$ 39万 - 项目类别:
Miscellaneous Programs