Essential Tremor: Gene expression profiling in cerebellar Purkinje cells
特发性震颤:小脑浦肯野细胞的基因表达谱
基本信息
- 批准号:8320096
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2014-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAgeAlzheimer&aposs DiseaseAnimal ModelAutopsyAxonBioinformaticsBiology of AgingBrainBrain regionCell modelCell physiologyCellsCellular biologyCerebellar cortex structureCerebellumCollectionComplexDataDegenerative DisorderDiseaseElderlyEssential TremorEvaluationEventFamilial TremorsFamilyFreezingFunctional disorderFunding MechanismsFutureGene ExpressionGene Expression ProfilingGenesGeneticGenomicsGliosisGoalsHereditary DiseaseHigh PrevalenceHumanHypertrophyIndividualInvestigationKineticsLabelLeadMethodsMetricModelingMolecularMovementMyoepithelial cellNerve DegenerationNeurogliaNeurologicNeuronsOutputParkinson DiseasePathogenesisPathologicPathologyPathway interactionsPatientsPatternPrevalenceProcessProteinsPurkinje CellsRNARecurrenceRegulationResearchResourcesSamplingScreening procedureSumSusceptibility GeneSwellingTimeTissuesTorpedoTransgenic MiceTremorUnited States National Institutes of Healtharmaxon regenerationbasecRNA Probesimprovedinterestlaser capture microdissectionmind controlnervous system disorderneuronal cell bodyneuronal survivalprospectivereceptorrepository
项目摘要
DESCRIPTION (provided by applicant): Essential tremor (ET) is among the most common neurological diseases, occurring in 4% of adults age 40 and older, and even more frequently in advanced age (i.e., 7-8% by age 70 and >20% by age 90+). Despite its high prevalence, the underlying pathogenesis of ET is poorly understood, and, as a consequence, current treatments are empiric and have poor efficacy. Human postmortem studies are currently the most robust avenue for advancing the study of the underlying pathophysiological mechanisms of ET, as genes have yet to be identified for ET, and no transgenic mice currently exist to provide an animal model. Our group has been conducting systematic postmortem studies, which have revealed identifiable structural changes in the brains of ET cases. We have demonstrated that neuropathologic findings in the vast majority of ET cases (>90%) localize to the cerebellum itself and, in particular, to the Purkinje cells (PC), which provide the entire neuronal output from cerebellar cortex. In ET brains, there is a 6- to 7-fold increase in damaged PC axons, identified as rounded swellings of the proximal portion of the PC axon (i.e., "torpedoes"). Strongly correlating with this PC axonal damage is an approximate 30-40% reduction in the number of PCs and an increase in the number of heterotopic (displaced) PCs. Our ongoing pathologic studies further indicates that the torpedo is likely only a marker of advanced PC axonal damage. Earlier changes are now becoming evident in ET brains, including a graded increase in small to intermediate-sized thickenings of the proximal PC axon (i.e., presumed precursor- torpedoes) and increases in PC recurrent axon collateral formation with increased sprouting along the intracortical segment of PC axons. These studies implicate PC degeneration as a core feature of the disease process in ET, associated with slowly progressive axonal damage and significant remodeling of intracortical cerebellar connectivity. While these postmortem studies have advanced our understanding of disease pathogenesis to a cellular level, it is time to now proceed to a molecular understanding. In this proposal, we will address whether molecular alterations can be identified in cerebellar PCs from ET patients vs. neurologically normal controls. We will perform gene expression analyses by microarray screening on RNA isolated from PCs of ET versus control autopsy brains. We will employ laser-capture microdissection to specifically target PCs, thereby facilitating a precise evaluation of cell-specific changes associated with ET. ET brains will be limited to those with an absence of other neurodegenerative pathologies at autopsy. Analysis of the resultant expression data will identify genes and/or molecular pathways that are differentially expressed and/or biologically grouped in ET versus control PCs. Changes in gene expression will be validated by quantitative real time PCR. This study will be the first to initiate a molecular expression approach in ET research, and will provide a basis for proposing molecular causal mechanisms for ET that will be the focus of future investigations.
描述(申请人提供):特发性震颤(ET)是最常见的神经系统疾病之一,发生在40岁及以上的成年人中的4%,甚至在高龄时更常见(即70岁时7-8%,90岁以上时20%)。尽管ET的发病率很高,但其潜在的发病机制尚不清楚,因此,目前的治疗方法是经验性的,疗效较差。人类死后研究是目前推进ET潜在病理生理机制研究的最有力的途径,因为ET的基因尚未确定,目前还没有转基因小鼠提供动物模型。我们小组一直在进行系统的尸检研究,揭示了ET病例大脑中可识别的结构变化。我们已经证明,绝大多数ET病例(>;90%)的神经病理结果局限于小脑本身,特别是浦肯野细胞(PC),它提供了小脑皮质的整个神经元输出。在ET脑中,受损的PC轴突增加了6到7倍,被识别为PC轴突近端的圆形肿胀(即“鱼雷”)。与PC轴突损伤密切相关的是PC数量减少约30%-40%,异位(移位)PC数量增加。我们正在进行的病理学研究进一步表明,鱼雷可能只是晚期PC轴突损伤的标志。早期的变化在ET脑中变得明显,包括近端PC轴突的中小型增厚(即推测为前体鱼雷)和PC再生轴突侧支形成增加,并沿PC轴突皮质内段发芽增加。这些研究表明,PC变性是ET疾病过程的核心特征,与缓慢进行性轴突损伤和皮质内小脑连接显著重塑相关。虽然这些尸检研究将我们对疾病发病机制的理解提高到了细胞水平,但现在是时候进行分子理解了。在这项提案中,我们将讨论在ET患者和神经学正常对照组的小脑PC中是否可以识别出分子变化。我们将通过微阵列筛选从ET患者和对照尸检脑组织中提取的RNA进行基因表达分析。我们将使用激光捕获显微解剖来专门针对PC,从而促进与ET相关的特定细胞变化的准确评估。ET的大脑将仅限于那些尸检时没有其他神经退行性病变的人。对结果表达数据的分析将识别在ET和对照PC中差异表达和/或生物学分组的基因和/或分子通路。基因表达的变化将通过实时定量聚合酶链式反应进行验证。这项研究将是首次在ET研究中启动分子表达方法,并将为提出ET的分子因果机制提供基础,这将是未来研究的重点。
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 }}
PHYLLIS L FAUST其他文献
PHYLLIS L FAUST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('PHYLLIS L FAUST', 18)}}的其他基金
Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration
深入探讨:绘制特发性震颤的神经病理学并探索神经退行性变的分子基础
- 批准号:
10210793 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor
特发性震颤中靶向小脑内质网钙处理
- 批准号:
10346058 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor
特发性震颤中靶向小脑内质网钙处理
- 批准号:
10541251 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration
深入探讨:绘制特发性震颤的神经病理学并探索神经退行性变的分子基础
- 批准号:
10553702 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration
深入探讨:绘制特发性震颤的神经病理学并探索神经退行性变的分子基础
- 批准号:
10378691 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
PATHOLOG-OMICS - ESSENTIAL TREMOR IN THE BROADER CONTEXT OF
病理组学 - 更广泛背景下的特发性震颤
- 批准号:
10307348 - 财政年份:2020
- 资助金额:
$ 20万 - 项目类别:
PATHOLOG-OMICS - ESSENTIAL TREMOR IN THE BROADER CONTEXT OF NEURODEGENERATION
病理组学 - 神经退行性更广泛背景下的特发性震颤
- 批准号:
8995706 - 财政年份:2015
- 资助金额:
$ 20万 - 项目类别:
PATHOLOG-OMICS - ESSENTIAL TREMOR IN THE BROADER CONTEXT OF NEURODEGENERATION
病理组学 - 神经退行性更广泛背景下的特发性震颤
- 批准号:
9213399 - 财政年份:2015
- 资助金额:
$ 20万 - 项目类别:
Essential Tremor: Gene expression profiling in cerebellar Purkinje cells
特发性震颤:小脑浦肯野细胞的基因表达谱
- 批准号:
8226636 - 财政年份:2011
- 资助金额:
$ 20万 - 项目类别:
CNS defects in a murine Zellweger syndrome model
小鼠齐薇格综合征模型中的中枢神经系统缺陷
- 批准号:
7237179 - 财政年份:1999
- 资助金额:
$ 20万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 20万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 20万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Grant-in-Aid for Scientific Research (C)