tRNA-derived non-coding RNAs in ASM function and in asthma
tRNA 衍生的非编码 RNA 在 ASM 功能和哮喘中的作用
基本信息
- 批准号:10643968
- 负责人:
- 金额:$ 58.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAllergicAllergic inflammationAnticodonAsthmaBiogenesisBiological MarkersBiological ModelsBronchoconstrictionCell ProliferationCell physiologyCellsCellular biologyDataDevelopmentEnzymesEpithelial CellsEtiologyFibroblastsFocal AdhesionsGene ExpressionGene Expression RegulationGoalsGonadal Steroid HormonesGrowth FactorHumanInflammationInflammation MediatorsInflammatory InfiltrateInhalationKnowledgeLigationLinkLungMalignant NeoplasmsMediatingMethodologyMethodsMolecularMorphologyMucous body substanceMusMuscle functionNeurodegenerative DisordersPathogenesisPathologyPathway interactionsPeriodicityPhenotypePhosphorylationPlasmaPlayProcessProductionProliferatingProtein Tyrosine KinaseProteinsPyroglyphidaeRNARNA analysisRegulationRegulator GenesResearchRibonucleasesRoleSamplingSignal PathwaySmooth Muscle MyocytesStressTranscriptional RegulationTransfer RNATranslational RegulationUntranslated RNAUp-Regulationairway epitheliumairway remodelingangiogeninasthmaticasthmatic patientbiological adaptation to stresscell growth regulationcell motilitychemokinechronic inflammatory diseasechronic inflammatory lung diseasecytokineexperienceindividual patientinorganic phosphateinsightmigrationnovelnovel therapeuticsoverexpressionposttranscriptionalpreventrespiratory smooth muscletranscriptometranscriptome sequencingtranscriptomic profiling
项目摘要
Project Summary and Abstract: The goal of our proposed studies is to elucidate the expression profiles and
molecular functions of short non-coding RNAs (ncRNAs) in the pathogenesis of asthma. Asthma is a chronic
inflammatory disease characterized by inflammation, mucus production, airway re-modeling, and hyper-
responsiveness. In asthma, allergic inflammatory mediators, such as cytokines, act on resident airway cells
[airway smooth muscle (ASM) cells, epithelial (AE) cells and fibroblasts (LF)] causing their structural and
functional changes. However, knowledge gaps remain in our understanding of the mechanisms by which
inflammatory mediators modulate cellular phenotypes. Although transcriptional regulation of gene expression in
resident airway cells has been extensively studied, regulatory mechanisms at post-transcriptional steps remain
elusive. In this context, short ncRNAs have evolved as one of the key post-transcriptional regulators of gene
expression. Previous transcriptome profiling for short ncRNA analyses relied mainly on standard RNA-seq
methods which fail to detect many RNA species. Cyclic phosphate-containing RNAs (cP-RNAs), that harbor a
cyclic phosphate (cP) at their 3′-end, are one such RNA species not captured by RNA-seq, because cP prevents
3′-adapter ligation. Their absence in RNA-seq data makes cP-RNAs an invisible, hidden component of
transcriptomes. Importantly, cP-RNAs are expressed as functional molecules. For example, angiogenin-
generated 5′-tRNA halves, containing a cP and thus belonging to cP-RNAs, have functional significance in stress
response, translational regulation, and cell proliferation, and are associated with neurodegenerative diseases
and cancers. We propose that 5′-tRNA halves and other cP-RNAs play important roles in asthma pathobiology.
In preliminary studies, we found that mouse lung expresses specific 5′-tRNA halves and cP-RNAs whose levels
are upregulated during allergic inflammation caused by inhaled challenge of house dust mite (HDM).
Furthermore, in human ASM cells, 5′-tRNA halves function to regulate cellular focal adhesion, migration, and
proliferation. These results allowed us to hypothesize that inflammatory mediators upregulate the levels of 5′-
tRNA halves/cP-RNAs, which contributes to airway cellular phonotypic changes in the molecular pathogenesis
of asthma. By using our developed cP-RNA-seq, we propose to fully elucidate the regulation of the expression
of 5′-tRNA halves/cP-RNAs mediated by asthmatic conditions in human lung and plasma samples and in human
ASM cells, AE cells, and LFs (Aim 1). We further propose to assess the functional effects of 5′-tRNA halves/cP-
RNAs on cellular focal adhesion, migration, proliferation, and morphology of ASM cells (Aim 2) and to investigate
the molecular mechanisms underlying the functional effects of those RNAs (Aim 3). The proposed studies will
reveal a novel ncRNA-engaged pathway in asthma pathogenesis and will support the exploration of biomarkers
in asthma.
项目摘要和摘要:我们建议的研究的目标是阐明表达谱和
短非编码RNA(NcRNAs)在哮喘发病机制中的分子功能哮喘是一种慢性疾病
炎症性疾病的特征是炎症、粘液产生、呼吸道重建和过度兴奋。
响应性。在哮喘中,过敏性炎症介质,如细胞因子,作用于驻留的呼吸道细胞。
[气道平滑肌(ASM)细胞、上皮(AE)细胞和成纤维细胞(LF)]引起它们的结构和
功能变化。然而,知识差距仍然存在于我们对机制的理解中
炎症介质调节细胞表型。尽管对基因表达的转录调控
驻留的呼吸道细胞已经被广泛研究,转录后步骤的调节机制仍然存在
难以捉摸。在这种背景下,短ncRNAs已经进化为基因转录后的关键调控因子之一
表情。以前用于短ncRNA分析的转录组图谱主要依赖于标准的rna-seq
无法检测到许多RNA物种的方法。环状含磷RNA(CP-RNAs),含有一种
环磷酸盐(CP)在其3‘端,是一种这样的RNA物种,不被RNA-seq捕获,因为CP阻止
3‘-接头结扎术。它们在RNA-seq数据中的缺失使得CP-RNA成为不可见的、隐藏的
抄本。重要的是,CP-RNA以功能分子的形式表达。例如,血管生成素-
生成的含有CP的5‘-tRNA半片段属于CP-RNAs,在胁迫中具有功能意义
反应、翻译调节和细胞增殖,并与神经退行性疾病相关
和癌症。我们认为5‘-tRNA半部分和其他CP-RNAs在哮喘的病理生物学中起重要作用。
在初步研究中,我们发现小鼠肺表达特异性的5‘-tRNA片段和CP-RNA,它们的水平
在吸入屋尘螨(HDM)引起的过敏性炎症过程中上调。
此外,在人ASM细胞中,5‘-tRNA调节细胞局部黏附、迁移和转移的功能减半。
扩散。这些结果允许我们假设炎症介质上调5‘-
TRNA减半/CP-RNAs,在分子发病机制中促进呼吸道细胞音型变化
哮喘的症状。通过使用我们开发的CP-RNA-seq,我们建议完全阐明表达的调节
哮喘条件对人肺、血浆和人体5‘-tRNA半组分/CP-RNAs的影响
ASM细胞、AE细胞和LFS(目标1)。我们进一步建议评估5‘-tRNA Halves/CP-的功能效应。
RNA对ASM细胞灶性黏附、迁移、增殖和形态的影响(目标2)并探讨
这些RNA功能效应的分子机制(目标3)。拟议的研究将
揭示ncRNA参与哮喘发病机制的新途径,并将支持生物标志物的探索
得了哮喘。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Infection-induced 5'-half molecules of tRNAHisGUG activate Toll-like receptor 7.
感染诱导的Trnahisgug的5 half分子激活类似收费的受体7。
- DOI:10.1371/journal.pbio.3000982
- 发表时间:2020-12
- 期刊:
- 影响因子:9.8
- 作者:Pawar K;Shigematsu M;Sharbati S;Kirino Y
- 通讯作者:Kirino Y
Making Invisible RNA Visible: Discriminative Sequencing Methods for RNA Molecules with Specific Terminal Formations.
- DOI:10.3390/biom12050611
- 发表时间:2022-04-20
- 期刊:
- 影响因子:5.5
- 作者:
- 通讯作者:
Crosstalk between diacylglycerol kinase and protein kinase A in the regulation of airway smooth muscle cell proliferation.
- DOI:10.1186/s12931-023-02465-8
- 发表时间:2023-06-10
- 期刊:
- 影响因子:5.8
- 作者:
- 通讯作者:
In vitro production and multiplex quantification of 2',3'-cyclic phosphate-containing 5'-tRNA half molecules.
- DOI:10.1016/j.ymeth.2021.04.024
- 发表时间:2022-07
- 期刊:
- 影响因子:0
- 作者:Kawamura T;Shigematsu M;Kirino Y
- 通讯作者:Kirino Y
{{
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 }}
Deepak A Deshpande其他文献
Deepak A Deshpande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('Deepak A Deshpande', 18)}}的其他基金
Optimizing function-selective ERK1/2 inhibitors for reducing AP-1-mediated airway pathology in asthma.
优化功能选择性 ERK1/2 抑制剂以减少 AP-1 介导的哮喘气道病理。
- 批准号:
10666887 - 财政年份:2023
- 资助金额:
$ 58.81万 - 项目类别:
tRNA-derived non-coding RNAs in ASM function and in asthma
tRNA 衍生的非编码 RNA 在 ASM 功能和哮喘中的作用
- 批准号:
10434062 - 财政年份:2020
- 资助金额:
$ 58.81万 - 项目类别:
Diacylglycerol kinase in airway smooth muscle functions
二酰甘油激酶在气道平滑肌功能中的作用
- 批准号:
10204427 - 财政年份:2019
- 资助金额:
$ 58.81万 - 项目类别:
Diacylglycerol kinase in airway smooth muscle functions
二酰甘油激酶在气道平滑肌功能中的作用
- 批准号:
10090626 - 财政年份:2019
- 资助金额:
$ 58.81万 - 项目类别:
Diacylglycerol kinase in airway smooth muscle functions
二酰甘油激酶在气道平滑肌功能中的作用
- 批准号:
10588000 - 财政年份:2019
- 资助金额:
$ 58.81万 - 项目类别:
Diacylglycerol kinase in airway smooth muscle functions
二酰甘油激酶在气道平滑肌功能中的作用
- 批准号:
10349442 - 财政年份:2019
- 资助金额:
$ 58.81万 - 项目类别:
Diacylglycerol kinase in airway smooth muscle functions
二酰甘油激酶在气道平滑肌功能中的作用
- 批准号:
9898459 - 财政年份:2019
- 资助金额:
$ 58.81万 - 项目类别:
Functional Diversity of Compartmentalized Calcium Signaling in Airway Smooth Muscle
气道平滑肌区室化钙信号传导的功能多样性
- 批准号:
9901263 - 财政年份:2017
- 资助金额:
$ 58.81万 - 项目类别:
Functional Diversity of Compartmentalized Calcium Signaling in Airway Smooth Muscle
气道平滑肌区室化钙信号传导的功能多样性
- 批准号:
10062409 - 财政年份:2017
- 资助金额:
$ 58.81万 - 项目类别:
Evaluation of novel substrate specific inhibitors of ERK1/2 in the treatment of asthma
新型ERK1/2底物特异性抑制剂治疗哮喘的评价
- 批准号:
9293245 - 财政年份:2016
- 资助金额:
$ 58.81万 - 项目类别:
相似海外基金
3-Dimensional genomic architecture in innate lymphoid cells and allergic inflammation
先天淋巴细胞和过敏性炎症的三维基因组结构
- 批准号:
10417585 - 财政年份:2022
- 资助金额:
$ 58.81万 - 项目类别:
The Effect of Allergic Inflammation on Ovarian Reserve Loss Associated with Endometrioma
过敏性炎症对子宫内膜异位症相关卵巢储备功能丧失的影响
- 批准号:
22K16884 - 财政年份:2022
- 资助金额:
$ 58.81万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The regulatory roles of basophils in skin allergic inflammation by using single-cell RNA-seq analysis
利用单细胞 RNA-seq 分析嗜碱性粒细胞在皮肤过敏性炎症中的调节作用
- 批准号:
22K07115 - 财政年份:2022
- 资助金额:
$ 58.81万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
3-Dimensional genomic architecture in innate lymphoid cells and allergic inflammation
先天淋巴细胞和过敏性炎症的三维基因组结构
- 批准号:
10650334 - 财政年份:2022
- 资助金额:
$ 58.81万 - 项目类别:
Regulators of Rho GTPases in allergic inflammation: Characterizing the role of RhoGDIs in the release of pro-inflammatory mediators from mast cells
过敏性炎症中 Rho GTP 酶的调节因子:表征 RhoGDI 在肥大细胞释放促炎介质中的作用
- 批准号:
475576 - 财政年份:2022
- 资助金额:
$ 58.81万 - 项目类别:
Studentship Programs
Human secreted IgD: structure, interactions and mechanisms in allergic inflammation and asthma
人类分泌的 IgD:过敏性炎症和哮喘的结构、相互作用和机制
- 批准号:
MR/V010557/1 - 财政年份:2021
- 资助金额:
$ 58.81万 - 项目类别:
Research Grant
The impact of exposure to allergic inflammation on esophageal carcinogenesis
接触过敏性炎症对食管癌发生的影响
- 批准号:
10308094 - 财政年份:2020
- 资助金额:
$ 58.81万 - 项目类别:
The impact of exposure to allergic inflammation on esophageal carcinogenesis
接触过敏性炎症对食管癌发生的影响
- 批准号:
10112399 - 财政年份:2020
- 资助金额:
$ 58.81万 - 项目类别:
Foxp3+ regulatory T cell-dependent treatment of allergic inflammation by glucocorticoids
Foxp3 调节性 T 细胞依赖性糖皮质激素治疗过敏性炎症
- 批准号:
10447598 - 财政年份:2020
- 资助金额:
$ 58.81万 - 项目类别:
Foxp3+ regulatory T cell-dependent treatment of allergic inflammation by glucocorticoids
Foxp3 调节性 T 细胞依赖性糖皮质激素治疗过敏性炎症
- 批准号:
10218031 - 财政年份:2020
- 资助金额:
$ 58.81万 - 项目类别: