MiR-193a-5p as a Regulator of Intersectin1-short and Clathrin-Mediated Endocytosis in Alzheimer's Disease.
MiR-193a-5p 作为阿尔茨海默病中 Intersectin1-short 和网格蛋白介导的内吞作用的调节剂。
基本信息
- 批准号:10288636
- 负责人:
- 金额:$ 4.95万
- 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:2021-09-05 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated Regions3xTg-AD mouseAbeta clearanceAddressAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer’s disease biomarkerAmyloid beta-ProteinAstrocytesAutopsyBindingBioinformaticsBiologicalBiological AssayBiological MarkersBrainBrain PathologyCause of DeathCellsCerebrospinal FluidClathrinDataDementiaDevelopmentDiagnosisDiseaseEndocytosisFunctional disorderFutureGene ExpressionGenetic TranscriptionGenomeHippocampus (Brain)HormonesHumanImmunoblot AnalysisIn Situ HybridizationIn VitroInjectionsKnowledgeLentivirus VectorLinkLiving DonorsLuciferasesMeasuresMediatingMessenger RNAMicroRNAsMicrogliaMusNerve DegenerationNeurofibrillary TanglesNeurologicNeuronsPathogenesisPathologyProcessProtein IsoformsProteinsPublishingRegulationReporterReportingRoleSamplingScaffolding ProteinSenile PlaquesSmall RNATestingTransferrinTranslationsUnited StatesWild Type Mousebioinformatics pipelinebrain cellbrain tissuecell typecirculating microRNAcoated pitcohortdifferential expressionfluorescence imagingfrontal lobein vivoinhibitor/antagonistinterestmicroRNA biomarkersmind controlmouse modelnovel therapeutic interventionoverexpressionprotein expressiontooluptake
项目摘要
PROJECT SUMMARY
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by the development of
amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain. Currently, the pathogenesis underlying AD is
unclear and there are no reliable tools to detect early changes in the brain. Studies in the Saugstad lab
revealed a specific set of microRNA (miRNA) biomarkers that are decreased in cerebrospinal fluid (CSF), and
which can classify AD patients from neurologically normal controls. MiRNAs regulate post-transcriptional gene
expression via complementary binding to sequences in mRNA that in turn regulate translation and expression
of the resulting protein. However, there is a knowledge gap regarding which mRNAs are targeted and
regulated by the AD CSF miRNAs and how these target proteins may contribute to AD pathophysiology. To
address this gap, I developed a bioinformatics pipeline to predict mRNA targets of the AD CSF miRNAs, and
identified Intersectin1-short (ITSN1-s) as a protein targeted by the AD CSF miRNA, miR-193a-5p. Immunoblot
analysis of human post mortem hippocampus showed significant increases in ITSN1-s protein in AD relative to
control. However, as ITSN1-s is expressed in multiple brain cell types, further studies that determine the
specific cell type(s) with increased ITSN1-s expression in AD are needed to examine potential mechanisms
underlying AD. Published studies report that ITSN-s is expressed in astrocytes and microglia, with low
expression in neurons, and that ITSN1-s functions to reduce clathrin-mediated endocytosis (CME). Microglia
have been shown to uptake fibrillar Aβ through a clathrin-mediated mechanism, and CME disruption in AD has
been linked to reduced Aβ clearance in neurons. However, it is not known whether ITSN1-s in microglia
contributes to this pathophysiology in AD. This proposal will assess the regulatory role of miR-193a-5p on
ITSN1-s and its functional significance in CME and AD. In order to accomplish this, I propose the following
aims: 1. establish the cellular expression of miR-193-a-5p and ITSN1-s in AD microglia and neurons; 2.
investigate the interaction between miR-193a-5p and ITSN1-s mRNA and the effects on ITSN1-protein
expression in vitro and in vivo; and 3. determine the role of miR-193a-5p levels on CME and Aβ uptake in AD
microglia. Ultimately, these studies will provide a deeper understanding of ITSN1-s regulation in AD and how
this may contribute to AD pathology. In addition, this framework can be used in future studies to evaluate the
biological consequences of circulating miRNA biomarkers in AD.
项目摘要
阿尔茨海默氏病(AD)是痴呆的最常见形式,其特征在于发展为:
淀粉样蛋白β(Aβ)斑块和大脑中的神经元缠结。目前,AD的发病机制是
目前还不清楚,也没有可靠的工具来检测大脑的早期变化。Saugstad实验室的研究
揭示了一组在脑脊液(CSF)中减少的特定microRNA(miRNA)生物标志物,
其可以将AD患者与神经学正常对照分类。miRNAs调控转录后基因
通过与mRNA中的序列互补结合来表达,所述mRNA中的序列反过来调节翻译和表达
产生的蛋白质。然而,关于哪些mRNA是靶向的,
受AD CSF miRNAs调控的研究以及这些靶蛋白如何参与AD病理生理学。到
为了解决这一差距,我开发了一个生物信息学管道来预测AD CSF miRNAs的mRNA靶点,
将Intersectin 1-short(ITSN 1-s)鉴定为AD CSF miRNA miR-193 a-5 p靶向的蛋白质。免疫印迹
人死后海马的分析显示,与对照组相比,
控制然而,由于ITSN 1-s在多种脑细胞类型中表达,进一步的研究表明,
需要AD中ITSN 1-s表达增加的特定细胞类型来研究潜在机制
基础AD已发表的研究报告称,ITSN-s在星形胶质细胞和小胶质细胞中表达,
ITSN 1-s的功能是减少网格蛋白介导的内吞作用(CME)。小胶质
已显示通过网格蛋白介导的机制摄取纤维状Aβ,AD中的CME破坏
与神经元中Aβ清除率降低有关。然而,目前尚不清楚小胶质细胞中的ITSN 1-s是否
有助于AD的病理生理学。该提案将评估miR-193 a-5 p对
ITSN 1-s及其在CME和AD中的功能意义为了做到这一点,我提出以下建议
目标:1.建立AD小胶质细胞和神经元中miR-193-a-5 p和ITSN 1-s的细胞表达; 2.
研究miR-193 a-5 p与ITSN 1-s mRNA的相互作用及其对ITSN 1-s蛋白的影响
体外和体内表达;和3.确定miR-193 a-5 p水平对AD中CME和Aβ摄取的作用
小胶质细胞最终,这些研究将提供更深入的了解ITSN 1-s在AD中的调节以及如何调节。
这可能有助于AD病理学。此外,这一框架可用于未来的研究,以评估
AD中循环miRNA生物标志物的生物学后果。
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 }}
Sierra Smith其他文献
Sierra Smith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('Sierra Smith', 18)}}的其他基金
MiR-193a-5p as a Regulator of Intersectin1-short and Clathrin-Mediated Endocytosis in Alzheimer's Disease.
MiR-193a-5p 作为阿尔茨海默病中 Intersectin1-short 和网格蛋白介导的内吞作用的调节剂。
- 批准号:
10480814 - 财政年份:2021
- 资助金额:
$ 4.95万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 4.95万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 4.95万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 4.95万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 4.95万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 4.95万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 4.95万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 4.95万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 4.95万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 4.95万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 4.95万 - 项目类别: