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.
项目总结
阿尔茨海默病(AD)是最常见的痴呆症形式,其特征是
大脑中的淀粉样β蛋白(Aβ)斑块和神经原纤维缠结。目前,AD的发病机制是
目前尚不清楚,也没有可靠的工具来检测大脑的早期变化。索格斯塔德实验室的研究
揭示了一组特定的microRNA(MiRNA)生物标记物,这些标记物在脑脊液(CSF)中减少
这可以将AD患者与神经学正常对照区分开来。MiRNAs调控转录后基因
通过与mRNA中的序列互补结合来表达,进而调节翻译和表达
所产生的蛋白质。然而,关于哪些mRNAs是靶向的,以及
由AD-CSF miRNAs调节,以及这些靶蛋白如何在AD病理生理学中起作用。至
为了解决这个问题,我开发了一条生物信息学管道来预测AD-CSF miRNAs的mRNA靶标,并且
Intersectin1-Short(ITSN1-S)是AD-CSFmiRNA(miR-193a-5p)的靶向蛋白。免疫印迹
对人死后海马区的分析表明,阿尔茨海默病患者ITSN1-S蛋白的表达显著高于对照组
控制力。然而,由于ITSN1-S在多种脑细胞类型中表达,进一步的研究确定了
需要特定的细胞类型(S)和ITSN1-S在AD中的表达增加来研究可能的机制
潜在的AD。已发表的研究报道,ITSN-S在星形胶质细胞和小胶质细胞中表达,低表达
研究结果表明,ITSN1-S基因在神经元中的表达具有抑制细胞骨架蛋白介导的内吞作用。小胶质细胞
已被证明通过网状蛋白介导的机制摄取纤维Aβ,而cME在AD中的破坏
与神经元中Aβ清除减少有关。然而,目前尚不清楚ITSN1-S是否存在于小胶质细胞中
对AD的这种病理生理学有贡献。该提案将评估miR-193a-5p对
ITSN1-S及其在继续医学教育和AD中的作用意义。为了实现这一目标,我提出以下建议
目的:1.建立miR-193-a-5p和ITSN1-S在AD小胶质细胞和神经元中的细胞表达;
研究miR-193a-5p与ITSN1-S的相互作用及其对ITSN1-蛋白的影响
3.确定miR-193a-5p水平对AD患者cME和Aβ摄取的影响。
小胶质细胞。最终,这些研究将对ITSN1-S在AD中的调控以及如何调控提供更深入的了解
这可能与AD的病理机制有关。此外,该框架可用于未来的研究,以评估
循环miRNA生物标记物在AD中的生物学后果。
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: