Deciphering the mechanisms of how the RAF/MEK/ERK pathway controls dendritic cell
Deciphering the mechanisms of how the RAF/MEK/ERK pathway controls dendritic cell
破译RAF/MEK/ERK通路控制树突状细胞的机制
批准号：
8988988
负责人：
Brandon Hogstad
金额：
$3.8万
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
项目状态：
已结题
起止时间：
2014-12-01 至 2016-11-30
关键词：
Antigen PresentationBRAF geneBone MarrowCD14 geneCandidate Disease GeneCell MaturationCell physiologyCellular biologyClinicalClinical TrialsCollaborationsDataDendritic CellsDevelopmentDiseaseDrug TargetingEosinophilic GranulomaFutureGene Expression ProfilingGoalsGranulomaHomeostasisHomologous GeneHumanITGAX geneImmuneInfectionLangerhans cellLesionLinkLiverLungMAPK14 geneMEKsMaintenanceMalignant NeoplasmsMediatingMolecularMolecular ProfilingMusMutationMyeloid CellsNeoplasmsPathogenesisPathway interactionsPatientsPediatric HospitalsPeripheralPhosphoric Monoester HydrolasesPhosphotransferasesPrevalenceProcessRegulationRegulatory T-LymphocyteReportingRoleRouteSignal PathwaySignal TransductionSkinSpecificitySpleenSyndromeT-Cell ActivationT-LymphocyteTNFRSF5 geneTestingTexasTherapeutic InterventionTissuesTreatment EfficacyValidationViral Oncogeneactionable mutationbonecohortdrug candidatehigh riskin vivoinsightlymph nodesmicrobialmigrationmouse modelmutantnew therapeutic targetnovelnovel therapeuticspromoterpublic health relevancesarcomastress activated protein kinasetargeted treatment
中文摘要
翻译
描述（由申请方提供）：朗格汉斯细胞组织细胞增生症（LCH）是一种人髓样细胞瘤形成，最近发现与病变中存在BRAFV 600 E突变相关。虽然以前不清楚这些BRAF突变是否只是乘客突变或发病机制的驱动因素，但我们的实验室最近建立了LCH的小鼠模型，证明树突状细胞中CD 11 c启动子下的BRAFV 600 E表达（CD 11 c-BRAFV 600 E）足以重现类似于高风险人类LCH的综合征。我们对CD 11 c-BRAFV 600 E树突状细胞的初步分析揭示了未成熟树突状细胞的致病性积累，其显示树突状细胞成熟/迁移标志物（MHCII、CD 40、CCR 7）表达减少，伴有树突状细胞（DC）中磷酸化ERK（pERK）增加。ERK抑制DC成熟和LCH发病机制的机制尚不清楚，但我们假设，有针对性地拯救DC成熟可能会为治疗临床LCH提供新的治疗选择。因此，在本提案的目标1和2中，我们的目标是描绘RAF/MEK/ERK途径抑制LCH小鼠模型中树突状细胞成熟的机制。在目标3中，我们将测试我们从目标2中识别的新型药物靶点的体内功效。通过这种方式，我们的目标是揭示调节DC成熟的新机制，并验证潜在的药物靶点，以指导新的LCH疗法的开发。
英文摘要
DESCRIPTION (provided by applicant): Langerhans Cell Histiocytosis (LCH) is a human myeloid cell neoplasia that has recently been associated with the presence of BRAFV600E mutations in lesions. Although it was previously unclear whether these BRAF mutations were simply passenger mutations or drivers of pathogenesis, our lab recently established a mouse model of LCH, demonstrating that BRAFV600E expression under the CD11c promoter in dendritic cells (CD11c-BRAFV600E) is sufficient to recapitulate a syndrome resembling high-risk human LCH. Our preliminary analysis of CD11c-BRAFV600E dendritic cells reveals pathogenic accumulation of immature dendritic cells displaying reduced expression of dendritic cell maturation/migration markers (MHCII, CD40, CCR7) accompanied by increased phospho-ERK (pERK) in dendritic cells (DC). The mechanisms linking ERK to suppression of DC maturation and LCH pathogenesis are not clear, but we hypothesize that targeted rescue of DC maturation may present novel therapeutic options for treating clinical LCH. Thus, in Aims 1 and 2 this proposal, our goal is to delineate the mechanism by which the RAF/MEK/ERK pathway suppresses dendritic cell maturation in a mouse model of LCH. In Aim 3, we will test the in vivo efficacy of novel drug targets that we identify from Aim 2. In this manner, our goal is to reveal novel mechanisms regulating DC maturation and validate potential drug targets to guide development of novel LCH therapies.
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