Elucidating the role of microglia and neurotrophin receptor p75 on neuronal degeneration in frontotemporal dementia
阐明小胶质细胞和神经营养蛋白受体 p75 在额颞叶痴呆神经元变性中的作用
基本信息
- 批准号:10328957
- 负责人:
- 金额:$ 19.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-15 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAreaAstrocytesAutopsyAwardBiological AssayBrainCell DeathCell NucleusCell SurvivalCell TransplantationCellsCellular StressCessation of lifeCoculture TechniquesCognitionComparative StudyControl GroupsDataDementiaDevelopmentDiseaseDown-RegulationFrontotemporal DementiaGene Expression ProfileGoalsHigh PrevalenceHistologicHumanImmunocompromised HostIn VitroIndividualInduced pluripotent stem cell derived neuronsInflammatoryInterleukin-18LanguageLigandsLinkMediatingMediator of activation proteinMicrogliaMolecular AnalysisMusNGFR ProteinNerve DegenerationNerve Growth Factor ReceptorsNeuraxisNeuritesNeurodegenerative DisordersNeurogliaNeuronsPathogenesisPathologicPathway interactionsPatientsPlayPopulationPredispositionRiskRoleSignal TransductionSiteSmall Nuclear RNAStressSubstantia nigra structureSurfaceTestingTherapeuticTissuesTrainingTransplantationbehavioral impairmentbrain tissuebrain-derived neurotrophic factor precursorcareer developmentcurative treatmentscytokineearly onsetfrontal lobegene correctionhuman stem cellsimaging studyimprovedin vivoinduced pluripotent stem cellinsightknock-downneurodegenerative dementianeuron lossneuronal survivalneurotrophic factornoveloverexpressionprogramsrelating to nervous systemsingle cell analysisstem cell modelsynaptogenesistau mutationtranscriptometranscriptome sequencing
项目摘要
Frontotemporal dementia (FTD) comprises a group of early-onset neurodegenerative diseases characterized by
widespread neuronal degeneration in the central nervous system leading to impairment of behavior, language
and cognition. As for other forms of dementias, mechanisms of neurodegeneration are only poorly understood
and curative treatment options still do not exist. There is growing evidence that non-cell-autonomous
mechanisms play an important role during disease development and that microglial cells significantly contribute
to pathologic changes in patients' brains. Microglial cells are strongly activated in the brains of patients with FTD
and their activation appears to be highest in areas of neuronal cell death. Also, imaging studies have
demonstrated that microglial activation begins early during disease development. Thus, it is very likely that
microglia directly contribute to neuronal degeneration in FTD, a role that has surprisingly been understudied in
the field. This K08 career development project sets out to elucidate such microglia-mediated, non-cell-
autonomous mechanisms of neurodegeneration by combining molecular analyses including single-nucleus RNA
sequencing in postmortem brain tissue with a dynamic human stem cell model of FTD using patient-derived
induced pluripotent stem cells (iPSCs). The overall goal of this study is to characterize changes in cellular
programs in neurons and microglia in FTD and to understand if and how patient microglia influence the integrity
of adjacent neurons in this disease. Encouraged by our preliminary data, we hypothesize that the neurotrophin
receptor p75NTR plays has an important role in this context by promoting death of neurons at risk. We also
propose that FTD-patient derived neurons carry an increased susceptibility to cell death that is further aggravated
by glia cells. This study will apply co-culture assays on iPSC-derived FTD and gene-corrected control neurons
in vitro (Specific Aim 1), transplantation of these cells into the brains of immunocompromised mice (Specific Aim
2) and single cell studies on postmortem brain tissue from FTD patients (Specific Aim 3). During the K08 Award
period, the applicant will also receive training in single-nucleus RNA sequencing on human cells and tissues
from patients with FTD. This project will advance our understanding of the role of microglia and neurotrophin
signaling in the pathogenesis of FTD with the long-term goal to better understand and potentially therapeutically
address the underlying mechanisms of this disease.
额颞叶痴呆(FTD)包括一组早发性神经退行性疾病,其特征在于
中枢神经系统中广泛的神经元变性,导致行为、语言
和认知。至于其他形式的痴呆症,神经退行性变的机制只是知之甚少
并且治愈性治疗选择仍然不存在。越来越多的证据表明,非细胞自主
这些机制在疾病发展过程中起着重要作用,小胶质细胞对疾病的发生和发展起着重要的作用。
病人大脑的病理变化FTD患者大脑中的小胶质细胞被强烈激活
并且它们的激活似乎在神经元细胞死亡的区域中最高。此外,影像学研究
表明小胶质细胞激活在疾病发展早期就开始了。因此,很可能
小胶质细胞直接导致FTD中的神经元变性,这一作用令人惊讶地未得到充分研究,
外地这个K08职业发展项目旨在阐明这种小胶质细胞介导的,非细胞的,
通过结合包括单核RNA在内的分子分析,
使用患者来源的FTD动态人干细胞模型对死后脑组织进行测序
诱导多能干细胞(iPSC)。本研究的总体目标是描述细胞内的变化,
FTD中神经元和小胶质细胞的程序,并了解患者的小胶质细胞是否以及如何影响完整性
相邻神经元的损伤受我们初步数据的鼓舞,我们假设神经营养因子
受体p75NTR通过促进处于危险中的神经元的死亡在这方面起重要作用。我们也
我提出,FTD患者衍生的神经元对细胞死亡的易感性增加,
神经胶质细胞。本研究将对iPSC衍生FTD和基因校正对照神经元进行共培养试验
在体外(特异性目标1),将这些细胞移植到免疫受损小鼠的脑中(特异性目标
2)FTD患者尸检脑组织的单细胞研究(特定目的3)。K08颁奖典礼
在此期间,申请人还将接受人体细胞和组织单核RNA测序的培训
FTD患者。这个项目将推进我们对小胶质细胞和神经营养因子的作用的理解
FTD发病机制中的信号传导,长期目标是更好地了解和潜在的治疗
解决这种疾病的潜在机制。
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 }}
Gunnar Hargus其他文献
Gunnar Hargus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('Gunnar Hargus', 18)}}的其他基金
Elucidating the Role of Microglia and Neurotrophin Receptor p75 on Neuronal Degeneration in Frontotemporal Dementia
阐明小胶质细胞和神经营养蛋白受体 p75 在额颞叶痴呆神经元变性中的作用
- 批准号:
10558666 - 财政年份:2021
- 资助金额:
$ 19.35万 - 项目类别:
Application of single cell sequencing to study astrocyte-mediated neuronal degeneration in a stem cell model of frontotemporal dementia
应用单细胞测序研究额颞叶痴呆干细胞模型中星形胶质细胞介导的神经元变性
- 批准号:
9806502 - 财政年份:2019
- 资助金额:
$ 19.35万 - 项目类别: