Deciphering the mechanisms of how the RAF/MEK/ERK pathway controls dendritic cell

 描述(申请人提供)：朗格汉斯细胞组织细胞增生症(LCH)是一种人类髓系细胞肿瘤，最近与病变中BRAFV600E突变的存在有关。尽管之前尚不清楚这些BRAF突变是乘客突变还是致病因素，但我们的实验室最近建立了LCH的小鼠模型，证明在CD11c启动子下树突状细胞(CD11c-BRAFV600E)中BRAFV600E的表达足以概括出一种类似于人类高危LCH的综合征。我们对CD11c-BRAFV600E树突状细胞的初步分析显示，未成熟树突状细胞在病理性堆积，表现为树突状细胞成熟/迁移标志物(MHCII、CD40、CCR7)表达减少，同时树突状细胞(DC)中磷酸化ERK(PERK)增加。ERK与抑制DC成熟和LCH发病的机制尚不清楚，但我们推测靶向挽救DC成熟可能为临床LCH的治疗提供新的治疗选择。因此，在目标1和2中，我们的目标是描述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中确定的新药物靶点的体内疗效。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。

 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.