Altered miRNA Expression Drives Proliferation of Lymphatic Malformation by Activating Pro-Growth Signaling Cascades
改变的 miRNA 表达通过激活促生长信号级联驱动淋巴畸形的增殖
基本信息
- 批准号:10677332
- 负责人:
- 金额:$ 3.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-25 至 2027-08-24
- 项目状态:未结题
- 来源:
- 关键词:AnatomyAngiopoietin-2Automobile DrivingBiological AssayBiologyBloodBlood VesselsCell ProliferationCell physiologyComplexData SetDermalDevelopmentDown-RegulationEndothelial CellsEnvironmentExcisionExclusionFunctional disorderGoalsGrowthGrowth FactorHomeostasisHumanInfiltrationInflammationIntegrinsInvestigationLaboratoriesLesionLifeLiposomesLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic MetastasisMediatingMediatorMentorsMessenger RNAMicroRNAsMolecularMolecular BiologyMorbidity - disease rateMultiomic DataMutationNuclearOperative Surgical ProceduresOutcomePIK3CA genePIK3CG genePainPathogenesisPathway interactionsPermeabilityPhenotypePhosphorylationPhysiciansPlasmidsPlayProliferatingProteinsProteomicsReceptor Protein-Tyrosine KinasesRecurrenceRegulationRoleScientistSclerotherapySignal TransductionSirolimusSmall Interfering RNAStructureSystems BiologyTestingTherapeuticTrainingTransfectionTubeUp-RegulationVascular Endothelial CellVascular PermeabilitiesWestern Blottingalpelisibcadherin 5careerclinical practicecongenital anomalydifferential expressiongain of functiongain of function mutationimmunocytochemistryimprovedinhibitorinsightknock-downlymphatic developmentlymphatic malformationslymphatic vesselmRNA sequencingmigrationmultidisciplinarymultiple omicsmutantnew therapeutic targetnoveloverexpressionpharmacologicposttranscriptionalprimary lymphedemaprotein expressiontargeted treatmenttherapeutic targettranscription factortranslational medicine
项目摘要
PROJECT SUMMARY/ABSTRACT
Lymphatic malformations (LMs) are complex congenital lesions composed of dilated, abnormal lymphatic
channels that can result in life-threatening morbidity due to their propensity to enlarge, encroach on nearby
anatomical structures, become infected, and cause significant pain and disfigurement. Although somatic, gain-
of-function mutations in the PIK3CA gene have been identified in LM endothelial cells (LM-ECs) and are thought
to drive aberrant lymphangiogenesis through overactivation of the PI3K/Akt pathway, the mechanisms underlying
many phenotypic abnormalities apparent in LMs, such as abnormal vessel formation and permeability, are not
fully understood. Considering the significant complications and recurrence rates of traditional treatments for LMs,
greater insight into the molecular mechanisms underlying LM pathogenesis is needed to identify novel
therapeutic targets and develop improved molecular therapies. Angiopoietin-2 (Ang-2) is a vascular growth factor
that plays a critical role in lymphatic development and homeostasis; however, its functions in LMs are unknown.
Utilizing a multi-omics approach (miRNA-seq, mRNA-seq, proteomics) to generate a comprehensive network of
miRNA-mRNA-protein expression in LM-ECs with gain-of-function PIK3CA mutations compared to normal
human dermal lymphatic endothelial cells, we have identified significant downregulation of Ang-2 mRNA and
protein in LM-ECs in parallel with significant upregulation of miRNAs in LM-ECs that are predicted post-
transcriptional suppressors of Ang-2, yet their function in LM-ECs is unknown. Ang-2 is also downregulated in
PIK3CA-mutant blood endothelial cells through Akt-mediated inactivation of its transcription factor, Forkhead box
O1. Ang-2 expression can be rescued with PI3K pathway inhibitors; however, this mechanism has not been
demonstrated in LMs. Considering the critical role of Ang-2 in lymphatic endothelial cell function, we hypothesize
that alternations in Ang-2 expression in LM-ECs drive their abnormal lymphangiogenic phenotype and may be a
viable therapeutic target. This hypothesis will be tested with the following specific aims: (1) define the regulatory
mechanisms driving differential expression of Ang-2 in LM-ECs and (2) define the impact of aberrant Ang-2
expression on LM-EC proliferation, migration, tube formation, and permeability. This proposal will be the first
investigation into the regulation and function of Ang-2 in LMs, potentially uncovering novel mechanisms
underlying the pathogenesis of LMs and lymphatic and vascular endothelial cell dysfunction which may improve
clinical practice and thus has significant relevance to the field of vascular biology. The overarching goal of this
proposal is to identify suitable targets for the development of deliverable, molecular therapeutics. The ACRI
Vascular Anomalies Laboratory provides an exceptional training environment, and we have assembled a
mentoring team of leaders in vascular anomalies, systems biology, and translational medicine that will facilitate
this unique and rigorous training, with the principal goal of preparing for a successful career as an independent
physician scientist.
项目摘要/摘要
淋巴管畸形(LMS)是一种复杂的先天性病变,由扩张、异常的淋巴管组成
可能导致危及生命的疾病的渠道,因为它们有扩大、侵占附近的倾向
解剖结构,被感染,并造成巨大的疼痛和毁容。虽然是躯体的,但收获-
PIK3CA基因的非功能突变已在光镜下内皮细胞(LM-ECs)中被发现,并被认为
通过PI3K/Akt通路的过度激活来驱动异常淋巴管生成,其机制
在LMS中,许多明显的表型异常,如异常的血管形成和通透性,没有
完全理解。考虑到传统治疗LMS的严重并发症和复发率,
需要对LM发病机制的分子机制有更深入的了解,以确定新的
治疗靶点,并开发改进的分子疗法。血管生成素2(Ang-2)是一种血管生长因子
它在淋巴发育和动态平衡中起着关键作用;然而,它在LMS中的功能尚不清楚。
利用多组学方法(miRNA-seq、mna-seq、蛋白质组学)生成一个全面的
功能增强型PIK3CA突变的LM-ECs中miRNA-mRNA-蛋白的表达
人皮肤淋巴管内皮细胞,我们发现Ang-2mRNA和Ang-2mRNA显著下调
Lm-ECs中的蛋白质与Lm-ECs中miRNAs的显著上调是平行的,这些miRNAs被预测在
Ang-2的转录抑制因子,但它们在Lm-ECs中的功能尚不清楚。血管紧张素转换酶-2在
通过Akt介导的转录因子Forkhead box失活PIK3CA突变的血液内皮细胞
O1.PI3K途径抑制剂可以挽救Ang-2的表达,然而,这一机制尚未得到证实
在LMS中演示。考虑到Ang-2在淋巴管内皮细胞功能中的关键作用,我们假设
Lm-ECs Ang-2表达的改变导致其淋巴管生成表型异常,可能是一种
可行的治疗靶点。这一假设将以以下具体目标进行检验:(1)定义监管
血管内皮细胞Ang-2差异表达的机制及(2)Ang-2异常表达的影响
Lm-EC增殖、迁移、管腔形成和通透性的表达。这项提议将是第一个
研究Ang-2在LMS中的调控和功能,可能揭示新的机制
LMS的发病机制和淋巴管和血管内皮细胞功能障碍可能会得到改善
临床实践,因此与血管生物学领域具有重要的相关性。这件事的首要目标是
建议是为可交付的分子疗法的开发确定合适的靶点。ACRI
血管异常实验室提供了一个特殊的培训环境,我们已经组装了一个
由血管异常、系统生物学和转化医学领域的领导者组成的指导团队将促进
这种独特而严格的训练,主要目标是为独立职业生涯的成功做准备
内科科学家。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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