Molecular phenotyping of cortical cell types in multiple rodent models of ALS
多种 ALS 啮齿动物模型中皮质细胞类型的分子表型
基本信息
- 批准号:9906956
- 负责人:
- 金额:$ 37.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinity ChromatographyAmericanAmyotrophic Lateral SclerosisAnatomyAnimal ModelArchitectureAstrocytesBasic ScienceBioinformaticsBrainBrain StemCandidate Disease GeneCell NucleusCellsCerebral cortexClinicalCollaborationsDiagnosisDiseaseDisease ProgressionDisease modelEarly InterventionEngineeringFamilial Amyotrophic Lateral SclerosisGene ExpressionGenesGenetic TechniquesGenetic studyGenomeHistologicHumanKnowledgeLabelLeadLinkMethodologyMethodsModelingMolecularMolecular AnalysisMolecular GeneticsMotorMotor Neuron DiseaseMotor NeuronsMouse StrainsMusMuscleMutationNerve DegenerationNeuronsNew YorkParalysedPathologic ProcessesPathologyPathway interactionsPatientsPlayPopulationProcessProteinsPyramidal CellsRNA analysisRNA purificationReport (document)ResearchResearch Project GrantsResourcesRibosomesRodent ModelRoleSignal PathwaySpinal CordTherapeuticTimeTransgenesTransgenic MiceTransgenic OrganismsTranslatingTranslationsUniversitiesVulnerable Populationsastrogliosiscell typecomparativeexperimental studyimprovedinnovationmolecular pathologymolecular phenotypemotor neuron degenerationmouse modelmutantneuron componentneuropathologynew therapeutic targetnovelpre-clinicalpre-clinical researchprogramsprotein TDP-43public health relevanceresponsesuccesssuperoxide dismutase 1therapeutic candidatetooltranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Over 30,000 Americans currently suffer from amyotrophic lateral sclerosis (ALS) which is characterized by progressive paralysis due to the degeneration of nerve cells in the brain and spinal cord that control muscles. Almost all cases of ALS are eventually fatal and the rapid progression of the disease makes it particularly terrible, with over 80% of patients dying within five years of diagnosis. No cure exists for ALS and the only available treatment slows disease progression by merely a few months. Therefore a great need exists for more effective and specific therapies that can stop or even reverse neurodegeneration. Innovation for such therapies will only arise from a better understanding of the molecular mechanisms underlying the pathological process. The proposed study aims to identify molecules and pathways dysregulated during disease progression in specific cell populations in the cerebral cortex, including the vulnerable "upper" motor neurons (UMNs). Such an analysis has never been done before due to the complexity of cortical architecture hampering the ability to distinguish between cell populations. Genetic studies have linked a number of genes to ALS pathology, including SOD1, TDP43, and FUS, yet all of these genes are widely expressed in many cell types throughout the body while ALS afflicts only certain cells in the CNS. This project will utilize the novel translating ribosome affinity purification (TRAP) methodology to overcome these limitations by allowing for the examination of protein translation from genetically defined cell types. Engineered mice harboring the TRAP transgene (bacTRAP mice) in four cortical cell types (two populations of vulnerable UMNs, a non-vulnerable neuronal population, and astrocytes) will be crossed to three mouse models of ALS that utilize disease-linked mutations in the SOD1 (G93A), TDP43 (M337V), and FUS (P525L) genes. These models recapitulate the neurodegeneration seen in human patients and will enable a comprehensive assessment of cell-type specific molecular changes during ALS pathology. Changes in gene expression during disease progression will be determined by analyzing TRAP translational profiles at three time points (early, pre-symptomatic, and late) within each model. While this is a
pre-clinical basic research project, efforts will be focused on identifying candidate genes that wil have the strongest and most immediate clinical impact. Particular emphasis will be placed on changes that occur at early and pre-symptomatic stages since earlier intervention will likely have an increased rate of success. These studies aim to improve upon the success rate of therapies arising from animal models by probing genes altered specifically in vulnerable cells across multiple models. Results from the proposed study will provide the field with a valuable resource of novel genes and signaling pathways to serve as candidate targets for more specific and innovative therapeutics to treat ALS.
描述(申请人提供):目前有超过30,000名美国人患有肌萎缩侧索硬化症(ALS),其特征是由于大脑和脊髓中控制肌肉的神经细胞退化而导致进行性瘫痪。几乎所有的肌萎缩侧索硬化症病例最终都是致命的,这种疾病的快速发展使其特别可怕,超过80%的患者在确诊后五年内死亡。肌萎缩侧索硬化症目前还没有治愈方法,唯一可用的治疗方法只是将疾病的进展延缓了几个月。因此,迫切需要更有效和更具体的治疗方法来阻止甚至逆转神经退行性变。只有更好地理解病理过程背后的分子机制,才能产生此类疗法的创新。这项拟议的研究旨在确定大脑皮层特定细胞群中疾病进展过程中失调的分子和途径,包括脆弱的“上层”运动神经元(UMN)。由于皮质结构的复杂性阻碍了区分细胞群体的能力,这样的分析在以前从未被做过。遗传学研究已经将一些基因与ALS的病理联系起来,包括SOD1、TDP43和FUS,然而所有这些基因在全身的许多细胞类型中都广泛表达,而ALS只影响中枢神经系统的某些细胞。该项目将利用新的翻译核糖体亲和纯化(TRAP)方法,通过允许检查来自遗传定义的细胞类型的蛋白质翻译来克服这些限制。在四种皮质细胞类型(两个脆弱的UMN群体、一个非脆弱的神经细胞群体和星形胶质细胞)中携带TRAP转基因的工程小鼠(bacTRAP小鼠)将与利用SOD1(G93A)、TDP43(M337V)和FUS(P525L)基因的疾病相关突变的三种ALS小鼠模型杂交。这些模型概括了人类患者的神经退行性变,并将能够全面评估ALS病理过程中细胞类型的特定分子变化。疾病进展过程中基因表达的变化将通过分析每个模型中三个时间点(早期、症状前期和晚期)的TRAP翻译图谱来确定。虽然这是一个
在临床前基础研究项目中,努力将重点放在确定将产生最强烈和最直接临床影响的候选基因上。将特别强调在早期和症状前阶段发生的变化,因为较早的干预可能会有更高的成功率。这些研究旨在通过探测多个模型中脆弱细胞中特定改变的基因,来提高动物模型产生的治疗的成功率。这项拟议研究的结果将为该领域提供宝贵的新基因和信号通路资源,作为治疗ALS的更具体和创新疗法的候选靶点。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Unique molecular features and cellular responses differentiate two populations of motor cortical layer 5b neurons in a preclinical model of ALS.
- DOI:10.1016/j.celrep.2022.110556
- 发表时间:2022-03-22
- 期刊:
- 影响因子:8.8
- 作者:Moya, Maria, V;Kim, Rachel D.;Rao, Meghana N.;Cotto, Bianca A.;Pickett, Sarah B.;Sferrazza, Caroline E.;Heintz, Nathaniel;Schmidt, Eric F.
- 通讯作者:Schmidt, Eric F.
Serotonin receptor 4 in the hippocampus modulates mood and anxiety.
- DOI:10.1038/s41380-020-00994-y
- 发表时间:2021-06
- 期刊:
- 影响因子:11
- 作者:Karayol R;Medrihan L;Warner-Schmidt JL;Fait BW;Rao MN;Holzner EB;Greengard P;Heintz N;Schmidt EF
- 通讯作者:Schmidt EF
{{
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 }}
Eric F Schmidt其他文献
Eric F Schmidt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('Eric F Schmidt', 18)}}的其他基金
Phenotyping Corticospinal Axon Degeneration in Preclinical ALS Models.
临床前 ALS 模型中皮质脊髓轴突变性的表型分析。
- 批准号:
10732637 - 财政年份:2023
- 资助金额:
$ 37.08万 - 项目类别:
Molecular Phenotyping of Cortical Cell Types in ALS-Related Neurodegeneration
ALS 相关神经变性中皮质细胞类型的分子表型
- 批准号:
10745149 - 财政年份:2023
- 资助金额:
$ 37.08万 - 项目类别:
Molecular phenotyping of cortical cell types in multiple rodent models of ALS
多种 ALS 啮齿动物模型中皮质细胞类型的分子表型
- 批准号:
9258507 - 财政年份:2016
- 资助金额:
$ 37.08万 - 项目类别:
Molecular Phenotyping of Cortical Cell Types in ALS Related Neurodegeneration
ALS 相关神经变性中皮质细胞类型的分子表型
- 批准号:
10592732 - 财政年份:2016
- 资助金额:
$ 37.08万 - 项目类别:
相似海外基金
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
- 批准号:
10506915 - 财政年份:2021
- 资助金额:
$ 37.08万 - 项目类别:
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
- 批准号:
10325006 - 财政年份:2021
- 资助金额:
$ 37.08万 - 项目类别:
SBIR Phase I: A New Class of Immobilized Metal Affinity Chromatography Resins
SBIR 第一阶段:一类新型固定金属亲和色谱树脂
- 批准号:
1746198 - 财政年份:2018
- 资助金额:
$ 37.08万 - 项目类别:
Standard Grant
Marine speciation of nickel using immobilized nickel affinity chromatography
使用固定镍亲和色谱法测定镍的海洋形态
- 批准号:
512537-2017 - 财政年份:2017
- 资助金额:
$ 37.08万 - 项目类别:
University Undergraduate Student Research Awards
I-Corps: Commercialization of Immobilized Metal Affinity Chromatography Resins Based on Nanomaterials
I-Corps:基于纳米材料的固定化金属亲和层析树脂的商业化
- 批准号:
1404605 - 财政年份:2014
- 资助金额:
$ 37.08万 - 项目类别:
Standard Grant
Antibody Purification via Affinity Chromatography that Utilizes the Unconventional Nucleotide Binding Site
利用非常规核苷酸结合位点通过亲和色谱法纯化抗体
- 批准号:
1263713 - 财政年份:2013
- 资助金额:
$ 37.08万 - 项目类别:
Continuing Grant
Development of multivalent DNA network based affinity chromatography diagnostics for isolating circulating tumour cells
开发基于多价 DNA 网络的亲和色谱诊断法,用于分离循环肿瘤细胞
- 批准号:
425749-2012 - 财政年份:2012
- 资助金额:
$ 37.08万 - 项目类别:
Postgraduate Scholarships - Master's
Next-Generation Affinity Chromatography with PEGylated Ligands
使用聚乙二醇化配体的新一代亲和色谱法
- 批准号:
1159886 - 财政年份:2012
- 资助金额:
$ 37.08万 - 项目类别:
Standard Grant
Immobilized zirconium ion affinity chromatography for specific enrichment of phosphoproteins
用于磷蛋白特异性富集的固定化锆离子亲和层析
- 批准号:
19560760 - 财政年份:2007
- 资助金额:
$ 37.08万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accelerating drug discovery using frontal affinity chromatography/mass spectrometry
使用正面亲和色谱/质谱加速药物发现
- 批准号:
234753-2000 - 财政年份:2003
- 资助金额:
$ 37.08万 - 项目类别:
Collaborative Research and Development Grants