Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease.
额颞叶痴呆和运动神经元疾病的深层病理表型。
基本信息
- 批准号:10220149
- 负责人:
- 金额:$ 86.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnatomyAnimal ModelAnteriorAntisense RNAAtrophicBiologicalBiologyBrainBrain regionC9ORF72Carrier ProteinsCell NucleusCellsComplexDNADNA BindingDNA DamageDataData SetDefectDipeptidesDiseaseEventExonsFrontotemporal DementiaGene ExpressionGene Expression ProfileGenesGeneticGoalsHistologicHistologyHumanImmunofluorescence ImmunologicIn SituIndividualLeadLibrariesLinkMeasuresMethodologyMethodsMinorityModelingMolecularMotor Neuron DiseaseMotor NeuronsNerve DegenerationNeurodegenerative DisordersNeuronsNuclearPathogenesisPathogenicityPathologicPathway interactionsPatientsPatternPhenotypeRAN GTPase Activating Protein 1RNARNA DegradationRNA markerRNA-Binding ProteinsResearchStreamSystemTestingTissuesUncertaintyWorkbasebehavioral variant frontotemporal dementiacell typedata archiveexperimental studyhuman diseasehuman tissueinnovationinsightloss of functionmultidimensional dataneuropathologynovelnucleocytoplasmic transportprotein TDP-43protein aggregationprotein biomarkerstherapeutic developmenttooltranscriptometranscriptome sequencingtranscriptomics
项目摘要
Abstract
This project seeks to perform deep pathological phenotyping of frontotemporal dementia (FTD) and motor
neuron disease (MND). The rationale for the proposal is that, despite the exploding basic biology of FTD
and MND, limited information is available about the strongest biological predictors of neurodegeneration
in the brains of patients. Even less is known about mechanisms underlying the striking selective
vulnerability seen in FTD and MND or what drives the clinico-anatomical overlap of the two disorders.
We will pursue these questions with a focus on TAR DNA-binding of 43 kDA (TDP-43) pathobiology, its
relationship to other emerging FTD/MND mechanisms, and its targeting of specific neuronal subtypes
within the FTD- and MND-related systems. We will further evaluate the complex neuropathological profile
seen in C9ORF72 expansion-related FTD/MND and build datasets equipped to help determine which
among the many pathological features in sporadic and C9-FTD/MND represent the strongest predictors
of neurodegeneration. Our approach seeks to overcome existing methodological barriers by combining
advanced histology, a novel tissue multiplexing platform that allows dozens of protein or RNA markers to
be quantified in situ, and single nucleus transcriptomics. We will study patients across the FTD/MND-
TDP-43 spectrum, including those with the C9ORF72 expansion, and control subjects. We aim to: (1)
Relate TDP-43 pathobiology to nuclear transport defects, cryptic exon incorporation, and DNA damage,
(2) Determine the pathological changes most prevalent in vulnerable neurons and regions and most
strongly linked to neurodegeneration, and (3) Identify transcriptional signatures of neuronal vulnerability
and TDP-43 pathobiology in FTD/MND. Successful completion of the proposed aims would resolve key
questions about the human relevance of candidate pathogenic mechanisms in FTD/MND-TDP, enabling
more informed prioritization of potential targets for human therapeutic development. The integrated
multidimensional data produced would create a deep library for testing new hypotheses as they emerge
and for generating new hypotheses. Finally, accomplishing our goals would advance a transformative
new histopathological approach to studying neurodegenerative and other complex human diseases.
摘要
该项目旨在对额颞叶痴呆(FTD)和运动性痴呆进行深层病理表型分析。
神经元疾病(MND)。该提案的基本原理是,尽管FTD的基础生物学正在爆炸,
和MND,关于神经变性最强的生物学预测因子的信息有限
在病人的大脑中。更少的是了解潜在的机制,罢工选择性
在FTD和MND中观察到的脆弱性,或者是什么驱动了这两种疾病的临床解剖学重叠。
我们将继续研究这些问题,重点是TAR DNA结合43 kDA(TDP-43)的病理生物学,
与其他新出现的FTD/MND机制的关系及其对特定神经元亚型的靶向作用
在FTD和MND相关系统中。我们将进一步评估复杂的神经病理学特征
在C9 ORF 72扩增相关FTD/MND中观察到,并构建数据集,以帮助确定
在散发性和C9-FTD/MND的许多病理学特征中,
神经退行性疾病我们的方法旨在克服现有的方法障碍,
先进的组织学,一种新的组织复用平台,允许几十种蛋白质或RNA标记物,
原位定量和单核转录组学。我们将研究FTD/MND中的患者-
TDP-43谱,包括C9 ORF 72扩增的受试者和对照受试者。我们的目标是:(1)
将TDP-43病理生物学与核转运缺陷、隐蔽外显子掺入和DNA损伤相关,
(2)确定在脆弱的神经元和区域中最普遍的病理变化,
与神经变性密切相关,以及(3)识别神经元脆弱性的转录特征
和FTD/MND中的TDP-43病理生物学。成功完成拟议目标将解决关键问题,
关于FTD/MND-TDP中候选致病机制的人类相关性的问题,
更明智地优先考虑人类治疗开发的潜在靶点。集成
产生的多维数据将创建一个深度库,用于测试新出现的假设
以及产生新的假设。最后,实现我们的目标将推进变革性的
研究神经退行性疾病和其他复杂人类疾病的新组织病理学方法。
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 }}
WILLIAM W SEELEY其他文献
WILLIAM W SEELEY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('WILLIAM W SEELEY', 18)}}的其他基金
Deep Pathological Phenotyping in Frontotemporal Dementia and Motor Neuron Disease.
额颞叶痴呆和运动神经元疾病的深层病理表型。
- 批准号:
10449356 - 财政年份:2018
- 资助金额:
$ 86.02万 - 项目类别:
Selective Vulnerability in Frontotemporal Dementia
额颞叶痴呆的选择性脆弱性
- 批准号:
8230564 - 财政年份:2009
- 资助金额:
$ 86.02万 - 项目类别:
Selective Vulnerability in Frontotemporal Dementia
额颞叶痴呆的选择性脆弱性
- 批准号:
8431393 - 财政年份:2009
- 资助金额:
$ 86.02万 - 项目类别:
Selective Vulnerability in Frontotemporal Dementia
额颞叶痴呆的选择性脆弱性
- 批准号:
7661740 - 财政年份:2009
- 资助金额:
$ 86.02万 - 项目类别:
相似海外基金
Linking Epidermis and Mesophyll Signalling. Anatomy and Impact in Photosynthesis.
连接表皮和叶肉信号传导。
- 批准号:
EP/Z000882/1 - 财政年份:2024
- 资助金额:
$ 86.02万 - 项目类别:
Fellowship
Digging Deeper with AI: Canada-UK-US Partnership for Next-generation Plant Root Anatomy Segmentation
利用人工智能进行更深入的挖掘:加拿大、英国、美国合作开发下一代植物根部解剖分割
- 批准号:
BB/Y513908/1 - 财政年份:2024
- 资助金额:
$ 86.02万 - 项目类别:
Research Grant
Simultaneous development of direct-view and video laryngoscopes based on the anatomy and physiology of the newborn
根据新生儿解剖生理同步开发直视喉镜和视频喉镜
- 批准号:
23K11917 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Genetics of Extreme Phenotypes of OSA and Associated Upper Airway Anatomy
OSA 极端表型的遗传学及相关上呼吸道解剖学
- 批准号:
10555809 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
computational models and analysis of the retinal anatomy and potentially physiology
视网膜解剖学和潜在生理学的计算模型和分析
- 批准号:
2825967 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Studentship
Computational comparative anatomy: Translating between species in neuroscience
计算比较解剖学:神经科学中物种之间的翻译
- 批准号:
BB/X013227/1 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Social and ecological influences on brain anatomy
博士论文研究:社会和生态对大脑解剖学的影响
- 批准号:
2235348 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Standard Grant
Development of a novel visualization, labeling, communication and tracking engine for human anatomy.
开发一种新颖的人体解剖学可视化、标签、通信和跟踪引擎。
- 批准号:
10761060 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Understanding the functional anatomy of nociceptive spinal output neurons
了解伤害性脊髓输出神经元的功能解剖结构
- 批准号:
10751126 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Anatomy and functions of LTP interactomes and their relationship to small RNA signals in systemic acquired resistance
LTP相互作用组的解剖和功能及其与系统获得性耐药中小RNA信号的关系
- 批准号:
BB/X013049/1 - 财政年份:2023
- 资助金额:
$ 86.02万 - 项目类别:
Research Grant