Characterizing Vulnerable Cell Types in C9orf72-FTD
表征 C9orf72-FTD 中的脆弱细胞类型
基本信息
- 批准号:10464266
- 负责人:
- 金额:$ 5.18万
- 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:2023-01-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAppearanceAutopsyBrainC9ORF72Cell NucleusCellsCessation of lifeChromiumComplexComputational TechniqueData SetDementiaDevelopmentDiseaseDisease ProgressionDisease associated microgliaEnvironmentExhibitsFemaleFormalinFrontotemporal DementiaFrontotemporal Lobar DegenerationsFunctional disorderFutureGene Expression ProfileGenesGeneticGenomicsGlutamatesGoalsHistological TechniquesHistologyHumanImmunofluorescence ImmunologicImmunohistochemistryIndividualInduced MutationInflammatoryKnockout MiceLeadLearningLesionLocationMapsMedialMethodsMicrogliaMolecularMolecular ProfilingMutationNerve DegenerationNeurodegenerative DisordersNeurogliaNeurologistNeuronsParaffin EmbeddingPathogenesisPathologicPatientsPhenocopyPhenotypePhysiciansPopulationRNARaceResearchScientistSlideSpatial DistributionStainsTechniquesTemporal LobeTestingTissue EmbeddingTissuesTrainingTranslational ResearchVulnerable Populationscell typeclinical phenotypeexcitatory neuronexcitotoxicityextracellularfrontal lobehuman tissuemaleneural networkneuroinflammationneuron lossnovelprotein TDP-43recruitresilienceresponsesexsuccesstargeted treatmenttranscriptometranscriptome sequencingtranscriptomics
项目摘要
Project Summary/Abstract
C9orf72 expansion mutations are the most common genetic cause of frontotemporal dementia (C9-FTD), a
fatal and incurable neurodegenerative disease. C9-FTD is most commonly neuropathologically characterized
by frontotemporal lobar degeneration (C9-FTLD) and the accumulation of phospho-TDP-43 (pTDP-43)
inclusions in neurons and glia. In C9-FTLD, the medial orbitofrontal cortex (mOFC) is affected early in the
disease course, and individuals with mOFC lesions phenocopy patients with FTD, suggesting that mOFC
dysfunction impacts FTD clinical phenotypes. In disease, the mOFC exhibits pTDP-43 inclusions, neuronal
degeneration, and neuroinflammation, including the development of pathologic microglia. In other diseases,
pathologic microglia increase extracellular glutamate and induce death in excitatory neurons. However, these
factors’ relative contributions to C9-FTLD pathogenesis are not well understood, and the molecular profiles of
degenerating neurons (termed vulnerable neurons) and pathologic microglia in the mOFC are unknown.
We hypothesize that in C9-FTLD, pathologic microglia contribute to the selective degeneration of
vulnerable populations of excitatory neurons, resulting in dementia. This proposal aims to use
transcriptomic methods to identify vulnerable neuron and pathologic microglia subtypes and characterize their
molecular profiles, spatial distributions, and interactions that may be contributing to disease progression. To
this end, Aim #1 will use single-nucleus RNA sequencing to identify and characterize the pathologic microglia
subtypes that arise and the vulnerable neuron subtypes that degenerate in C9-FTLD. Cellular proximity is the
basis for intercellular interactions, and Aim #2 will use spatial transcriptomics to identify where these pathologic
microglia and vulnerable neurons are spatially distributed as well as their spatial proximities in relation to each
other and to pTDP-43 inclusions.
A better understanding of how C9-FTLD changes neurons’ and microglia’s gene expression patterns, their
spatial distributions, and their interactions may lead to strategies to protect cells from disease and patients
from dementia. These studies will emphasize how pathologic microglia can contribute to neurodegeneration,
enabling the development of microglia-targeted therapies for C9-FTD and other neurodegenerative diseases.
Through this project, I will develop expertise in the use of histological and computational techniques. My
sponsor, Dr. Edward Lee, is committed to my training and success as a physician-scientist.
项目摘要/摘要
C9ORF72扩增突变是额颞叶痴呆(C9-FTD)最常见的遗传原因,
致命且无法治愈的神经退行性疾病。C9-FTD是最常见的神经病理学特征。
额颞叶变性(C9-FTLD)和磷酸化TDP-43(pTDP-43)的积聚
神经元和神经胶质细胞内的包涵体。在C9-FTLD中,内侧眶前皮质(MOFC)在早期就受到影响
病程与个体mOFC皮损表现为FTD患者有关,提示mOFC
功能障碍影响FTD的临床表型。在疾病中,mOFC显示pTDP-43包涵体,神经元
变性和神经炎症,包括病理性小胶质细胞的发展。在其他疾病中,
病理性小胶质细胞增加细胞外谷氨酸,导致兴奋性神经元死亡。然而,这些
因素在C9-FTLD发病机制中的相对作用尚不清楚,其分子图谱
MOFC中的变性神经元(称为脆弱神经元)和病理性小胶质细胞尚不清楚。
我们推测,在C9-FTLD中,病理性小胶质细胞参与了选择性退变。
易受伤害的兴奋性神经元群体,导致痴呆。这项提案旨在利用
转录学方法鉴定易损神经元和病理性小胶质细胞亚型及其特征
可能导致疾病进展的分子概况、空间分布和相互作用。至
为此,目标1将使用单核RNA测序来识别和表征病理性小胶质细胞
C9-FTLD中出现的亚型和退化的脆弱神经元亚型。蜂窝接近性是
细胞间相互作用的基础,Aim#2将使用空间转录切割技术来确定这些病理
小胶质细胞和脆弱神经元在空间上的分布以及它们之间的空间邻近性
其他和pTDP-43包裹体。
更好地了解C9-FTLD如何改变神经元和小胶质细胞的基因表达模式,他们的
空间分布及其相互作用可能导致保护细胞免受疾病和患者伤害的策略
得了痴呆症。这些研究将强调病理性小胶质细胞如何促进神经变性,
能够开发针对C9-FTD和其他神经退行性疾病的小胶质细胞靶向疗法。
通过这个项目,我将在组织学和计算技术的使用方面发展专业知识。我的
赞助商爱德华·李博士致力于我作为一名内科科学家的培训和成功。
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 }}
David Dai其他文献
David Dai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
AMFaces: Advanced Additive Manufacturing of User-Focused Facial Prostheses with Real-Life Colour Appearance
AMFaces:以用户为中心的面部假体的先进增材制造,具有真实的色彩外观
- 批准号:
EP/W033968/1 - 财政年份:2023
- 资助金额:
$ 5.18万 - 项目类别:
Research Grant
Understanding the appearance mechanism of ferroelectric liquid crystals showing spontaneous polarization in the director and developing their applications.
了解铁电液晶在指向矢中表现出自发极化的出现机制并开发其应用。
- 批准号:
23H00303 - 财政年份:2023
- 资助金额:
$ 5.18万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Elucidating the mechanism in the color appearance of small-field stimulus on chromatic surroundings
阐明彩色环境中小场刺激的颜色外观机制
- 批准号:
22K20317 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
Body, appearance, and health surveillance in female youth friendship contexts
女性青少年友谊背景下的身体、外表和健康监测
- 批准号:
2690554 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
Studentship
Learning to Recognize Faces Despite Within-Person Variability in Appearance: A Developmental Approach
尽管人与人之间的外表存在差异,但仍要学习识别面孔:一种发展方法
- 批准号:
RGPIN-2022-04386 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
Discovery Grants Program - Individual
Path-space Exploration for Light Transport and Appearance Modelling
光传输和外观建模的路径空间探索
- 批准号:
RGPIN-2018-05669 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
Discovery Grants Program - Individual
Appearance of negative influences of global warming on crop production and measures against it
全球变暖对农作物生产的负面影响的显现及应对措施
- 批准号:
21H02330 - 财政年份:2021
- 资助金额:
$ 5.18万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
A sociological study on appearance discrimination during employment selection
就业选择中外表歧视的社会学研究
- 批准号:
21K13447 - 财政年份:2021
- 资助金额:
$ 5.18万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The influence of river environment on urban appearance of wildlife
河流环境对野生动物城市面貌的影响
- 批准号:
21K12322 - 财政年份:2021
- 资助金额:
$ 5.18万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Method for assessing women's perceptions of their appearance in the context of breast cancer care
评估乳腺癌护理背景下女性对其外表的看法的方法
- 批准号:
10196213 - 财政年份:2021
- 资助金额:
$ 5.18万 - 项目类别: