Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression
痣相关的 microRNA 作为 BRAF 诱导的生长停滞的介质和黑色素瘤进展的生物标志物
基本信息
- 批准号:10807912
- 负责人:
- 金额:$ 5.99万
- 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:2021-08-24 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AnatomyAreaAutomobile DrivingBRAF geneBenignBiological AssayBiological ModelsBiologyBiopsyChemopreventionClassificationClinicalClustered Regularly Interspaced Short Palindromic RepeatsData SetDermatologistDevelopmentDiseaseDrug Delivery SystemsEarly DiagnosisEngineeringEventGenesGeneticGrowthHumanHuman EngineeringIn VitroKnowledgeLesionMediatorMelanocytic nevusMicroRNAsMole the mammalMolecular ProfilingNeoplasmsNevi and MelanomasNevusPhysiciansPilot ProjectsPositioning AttributePreventionPrevention strategyReportingReproducibilitySkin CancerSkin PigmentationSystemTechniquesTrainingTranscriptValidationaurora B kinasedetection methoddiagnostic accuracydifferential expressiondriver mutationhigh risk populationin vivoin vivo Modelmelanocytemelanomamelanoma biomarkersmiRNA expression profilingnovelpre-clinicalpreventscreeningskin lesiontumor
项目摘要
Summary
A single driver mutation, BRAFV600E, drives half of all melanomas. However, in the majority of cases,
acquisition of BRAFV600E instead drives benign tumors, such as melanocytic nevi (the common mole). We seek
to decipher the intracellular mechanisms that prevent full transformation, and harness this knowledge to
develop candidate early diagnosis and chemoprevention strategies. We have discovered a signature of
microRNAs (miRNA) as the most differentially expressed transcripts distinguishing nevi from either normal
melanocytes or melanomas. We have reported that expression of these miRNAs classifies biopsied pigmented
neoplasms with high diagnostic accuracy. To determine whether knowledge of these miRNAs could aid in the
prevention of melanoma: First, we conducted a comprehensive identification and functional screen of the
targets of the most predictive miRNA, MIR211-5p. Using freshly isolated and CRISPR engineered human
normal, nevus and melanoma melanocytes, we identified inhibition of AURKB expression as a critical
mechanism driving both BRAFV600E and MIR211-5p associated growth arrest in vitro. Therefore, in Aim 1, our
objective is to assess the roll of the MIR211-5p/AURKB axis in nevus formation and transformation in vivo, and
the efficacy of disrupting this axis in melanoma chemoprevention. Second, we generated a non-invasive assay
for miRNA screening of pigmented lesions prior to biopsy. In a small pilot study, we found the high accuracy of
classification of melanocytic neoplasia was retained. In Aim 2, our objective is to validate the utility of using
non-invasive profiling of the miRNA signature to screen pigmented skin lesions.
Three advances distinguish our proposal. The first is the reproducibility of our miRNA classifier, currently
validated on six independent datasets. Second, our model systems for this disease—engineered primary
human melanocytes, nevi, and melanomas, combined with an in vivo system that recapitulates both the
genetics and progression of melanoma—puts us in a unique position to control for context-specific effects
when studying these critical events. Third, is our development of a non-invasive miRNA profiling assay, a
molecular profiling technique that is both non-invasive and lesion-specific. Our team, consisting of experts in
both the basic biology of miRNA and melanoma, in vivo models of melanoma, topical drug delivery, and the
daily practice of melanoma surveillance, allows us to comprehensively tackle this project.
This project has both basic and clinical potential significance. Our studies explore novel explanations for nevus
initiation, driven by observations made from clinical lesions. We expect these studies to directly result in an
increase in the early detection of melanomas and preclinical validation of a strategy for topical
chemoprevention for particularly high-risk individuals and/oror anatomic areas.
总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert Laird Judson-Torres其他文献
Robert Laird Judson-Torres的其他文献
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{{ truncateString('Robert Laird Judson-Torres', 18)}}的其他基金
Development and Pre-Clinical Validation of Quantitative Imaging of Cell State Kinetics (QuICK) for Functional Precision Oncology
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- 批准号:
10737379 - 财政年份:2023
- 资助金额:
$ 5.99万 - 项目类别:
Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression
痣相关的 microRNA 作为 BRAF 诱导的生长停滞的介质和黑色素瘤进展的生物标志物
- 批准号:
10292583 - 财政年份:2021
- 资助金额:
$ 5.99万 - 项目类别:
Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression
痣相关的 microRNA 作为 BRAF 诱导的生长停滞的介质和黑色素瘤进展的生物标志物
- 批准号:
10684681 - 财政年份:2021
- 资助金额:
$ 5.99万 - 项目类别:
Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression
痣相关的 microRNA 作为 BRAF 诱导的生长停滞的介质和黑色素瘤进展的生物标志物
- 批准号:
10474476 - 财政年份:2021
- 资助金额:
$ 5.99万 - 项目类别:
MicroRNA-Based Detection of Barriers to Melanoma Progression
基于 MicroRNA 的黑色素瘤进展障碍检测
- 批准号:
8927090 - 财政年份:2014
- 资助金额:
$ 5.99万 - 项目类别:
MicroRNA-Based Detection of Barriers to Melanoma Progression
基于 MicroRNA 的黑色素瘤进展障碍检测
- 批准号:
9349379 - 财政年份:2014
- 资助金额:
$ 5.99万 - 项目类别:
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