The Role of sEV-associated miR-146a in Tissue Repair
sEV 相关 miR-146a 在组织修复中的作用
基本信息
- 批准号:10538174
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-27 至 2024-09-26
- 项目状态:已结题
- 来源:
- 关键词:AccelerationBiologicalBiological AssayCadherinsCell LineCellsClinical TrialsDataDermatologicDevelopmentDiabetes MellitusDiabetic mouseEncapsulatedEngineeringEnvironmentEpidermal Growth Factor ReceptorEpidermisEventExpenditureGenesGoalsHealthcareHyperplasiaInflammatory ResponseLeadMalignant - descriptorMalignant Epithelial CellMediatingMedicareMessenger RNAMicroRNAsModalityNatureOutcomePathologyPathway interactionsPlayPoriferaProcessProteinsPsoriasisRNARegulationResearchRoleSRC geneSignal TransductionSignaling MoleculeSquamous cell carcinomaSubcutaneous InjectionsSupplementationSystemUp-RegulationVesicleWestern BlottingWorkWound healing therapychronic wounddesmoglein 2diabetic wound healingexperimental studyextracellular vesicleshealinginhibitorinterestkeratinocytemetaplastic cell transformationmigrationmouse modelnoveloverexpressionpreventresponseskin woundtissue regenerationtissue repairtranscriptometranscriptome sequencingtumortumorigenesiswoundwound closurewound healingwound treatment
项目摘要
ABSTRACT
Cutaneous wounds represent a significant healthcare issue and since 1997, no treatment for chronic wounds
has received FDA approval. Contributing to this treatment desert is the complexity of the wound healing process
and the relatively understudied field of how these activities are dysregulated and exploited in chronic wounds
and cellular transformation. Our previous work demonstrated that the cadherin, desmoglein 2 (Dsg2) is a
pleiotropic protein that modulates mitogenic signaling and pro-migratory programming in both tumorigenesis and
wound healing. We have shown that Dsg2 is down-regulated in chronic wounds and that constitutive
overexpression of Dsg2 in the epidermis confers increased wound healing, hyperproliferation, and tumor
development. Highlighting the contribution of altered keratinocyte dynamics to the pathology of many
dermatological conditions including chronic wounds, psoriasis, and squamous cell carcinoma. Dsg2 is able to
modulate keratinocyte activities such as proliferation and migration through its regulation of downstream
signaling molecules including the pro-proliferative and migratory proteins: EGFR and c-Src. In addition to the
modulation of proteins, our lab has also demonstrated that Dsg2 regulates the cellular and small extracellular
vesicle (sEV) transcriptome. miRNAseq revealed that Dsg2 induced the dramatic depletion of miR-146a, which
is a potent regulator of the inflammatory response and has been shown to potentially regulate 4469 genes,
including the level of miR-155. Therefore, it was interesting to note the consequent increase of miR-155 in
response to Dsg2 expression. Recently, we have focused on identifying the upstream regulators of Dsg2, and
much to our surprise, miR-155 targets Dsg2, which should lead to its degradation, however, RNAseq of these
same cells lead to the realization that the level of the lncRNA, Dsg2-AS1, was also increased. It is well
established that lncRNAs can “sponge” miRNAs and inhibit the degradation of their targets. This led us to
consider a novel regulatory mechanism whereby Dsg2-AS1 sponges miR-155, allowing for a dramatic increase
in Dsg2 expression. Preliminary data demonstrates that this mechanism is at play during normal wound healing,
as evidenced by the increase in Dsg2 expression after the concomitant increase of miR-155 and Dsg2-AS1
during wound repair. In this proposal, we hypothesize that the regulatory loop that controls Dsg2 expression is
altered in chronic wounds such as in the context of diabetes, which results in perturbed keratinocyte activation
and therefore ineffective wound closure. Thus, the goals of this proposal are to elucidate the Dsg2 regulatory
network and its impact on keratinocyte proliferation and migration, and to demonstrate the ability of sEV-
encapsulated RNA species that target this network as a way to stimulate keratinocyte activation in wound repair.
The findings obtained from these studies will demonstrate the feasibility of sEVs as a robust treatment modality
and contribute to the mechanistic understanding of wound healing.
摘要
皮肤伤口是一个重要的医疗保健问题,自1997年以来,没有治疗慢性伤口
已获得FDA批准。造成这种治疗沙漠的原因是伤口愈合过程的复杂性
以及这些活动在慢性伤口中是如何失调和利用的相对欠研究的领域
和细胞转化。我们以前的工作表明,钙粘蛋白,桥粒芯糖蛋白2(Dsg 2)是一个
一种多效性蛋白,在肿瘤发生和转移中调节促有丝分裂信号和促迁移程序,
伤口愈合我们已经表明,Dsg 2在慢性伤口中下调,并且组成性的
表皮中Dsg 2的过表达赋予伤口愈合、过度增殖和肿瘤生长的增加。
发展强调了角质形成细胞动力学改变对许多肿瘤病理学的贡献,
皮肤病,包括慢性伤口、牛皮癣和鳞状细胞癌。DSG 2可以
调节角质形成细胞的活动,如增殖和迁移,通过其调节下游
信号分子包括促增殖和迁移蛋白:EGFR和c-Src。除了有
我们的实验室还证明,Dsg 2调节细胞和小的细胞外蛋白质,
囊泡(sEV)转录组。miRNAseq揭示Dsg 2诱导miR-146 a的显著消耗,
是炎症反应的有效调节剂,并已显示潜在调节4469个基因,
包括miR-155的水平。因此,有趣的是,注意到miR-155的随之增加,
对Dsg 2表达的应答。最近,我们专注于鉴定Dsg 2的上游调节因子,
令我们惊讶的是,miR-155靶向Dsg 2,这应该导致其降解,然而,这些的RNAseq
相同的细胞导致lncRNA,Dsg 2-AS 1的水平也增加的认识。公
确立了lncRNA可以“海绵”miRNA并抑制其靶标的降解。这导致我们
考虑一种新的调节机制,Dsg 2-AS 1海绵miR-155,允许急剧增加
在Dsg 2表达中。初步数据表明,这种机制在正常伤口愈合过程中起作用,
如在miR-155和Dsg 2-AS 1同时增加后Dsg 2表达增加所证明的
在伤口修复过程中。在这个提议中,我们假设控制Dsg 2表达的调节环是
在慢性伤口中改变,例如在糖尿病的情况下,这导致角质形成细胞活化受到干扰
从而导致无效的伤口闭合。因此,本提案的目标是阐明Dsg 2调节性的作用。
网络及其对角质形成细胞增殖和迁移的影响,并证明sEV-
包封的RNA种类靶向该网络作为刺激伤口修复中角质形成细胞活化的方式。
从这些研究中获得的结果将证明sEV作为一种稳健治疗方式的可行性
并有助于理解伤口愈合的机制。
项目成果
期刊论文数量(0)
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Brianna Leigh Hill其他文献
Brianna Leigh Hill的其他文献
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{{ truncateString('Brianna Leigh Hill', 18)}}的其他基金
The Role of sEV-associated miR-146a in Tissue Repair
sEV 相关 miR-146a 在组织修复中的作用
- 批准号:
10734048 - 财政年份:2022
- 资助金额:
$ 4.68万 - 项目类别:
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