Identifying a nodal point for G alpha q signaling in eye disease
Identifying a nodal point for G alpha q signaling in eye disease
批准号:
9006784
负责人:
DEAN Yaw LI
金额:
$34.08万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-01-01 至 2020-12-31
关键词:
BRAF geneBindingBiological AssayBlood VesselsCause of DeathCell NucleusCell membraneChoroidCutaneous MelanomaDataDiseaseEyeEye NeoplasmsEye diseasesFZD4 geneG alpha q ProteinG(q) AlphaGNAQ geneGene SilencingGenetic TranscriptionGlaucomaGrowthHealthHumanIn VitroIndividualLiverLungMAP Kinase GeneMalignant NeoplasmsMediatingMelanoma CellMethodsMolecular TargetMonomeric GTP-Binding ProteinsMutationNeoplasm MetastasisNodalNuclear TranslocationOncogenicOrganPathway interactionsPatientsPharmacotherapyPhospholipase CPlayProtein Kinase CProteinsRNA InterferenceResearch PersonnelRetinaRoleRunningSignal PathwaySignal TransductionSignaling ProteinStructure of lamina episcleralisSturge-Weber SyndromeTestingTherapeuticTranscription Factor AP-1Uveal MelanomaWNT Signaling PathwayWNT5A geneXenograft ModelXenograft procedurebaseconjunctivadrug developmenteffective therapyin vivoin vivo Modelknock-downmalformationmouse modelsmall hairpin RNAsmall moleculesmall molecule inhibitortherapeutic targettraffickingtumortumorigenesis
中文摘要
描述(由申请人提供):在大约80%的葡萄膜黑色素瘤中,两个q类(Gαq)的Gα蛋白GNAQ和GNA11的激活突变是肿瘤发生的驱动因素。在Sturge-Weber综合征患者中也发现了类似的GNAQ激活突变,该综合征可表现为青光眼和结膜、脉络膜、视网膜和巩膜外血管畸形。葡萄膜黑色素瘤是最常见的原发性眼部肿瘤,在大约50%的病例中,肿瘤会转移到其他器官,主要是肝脏。一旦转移,这种疾病总是致命的。激活GNAQ和GNA11突变通过控制最近发现的几种信号通路来驱动葡萄膜黑色素瘤的发生,包括磷脂酶C- β /蛋白激酶C (PLC- β /PKC)和TRIO-RhoA/Rac1通路,它们激活MAPK/ERK和YAP,诱导AP1和YAP- tead介导的转录。然而,机制(s)由
英文摘要
DESCRIPTION (provided by applicant): Activating mutations in two Gα proteins of the q class (Gαq), GNAQ and GNA11, are the drivers of oncogenesis in approximately 80% of uveal melanomas. Similar activating mutations of GNAQ are also found in patients with Sturge-Weber syndrome, which can manifest itself as glaucoma and vascular malformations of the conjunctiva, choroid, retina, and episclera. Uveal melanoma is the most common primary ocular tumor, and in approximately 50% of the cases, the tumor will metastasize to other organs, primarily the liver. Once metastasized, the disease is invariably fatal. Activating GNAQ and GNA11 mutations drive uveal melanoma oncogenesis via the control of several recently identified signaling pathways, including phospholipase C-ß/protein kinase C (PLC-ß/PKC) and TRIO-RhoA/Rac1 pathways, which activate MAPK/ERK and YAP to induce AP1- and YAP-TEAD-mediated transcription. However, the mechanism(s) by
which Gαq proteins activate multiple downstream pathways has not been completely elucidated. Preliminary data suggest that the small GTPase ARF6 may act as an immediate downstream effector of activated GNAQ/GNA11 to control all of the currently known oncogenic Gαq signaling pathways. Other preliminary data also suggest that Gαq may signal through ARF6 to activate ß-catenin signaling by promoting the relocalization of ß-catenin from the cell membrane to the nucleus where it can mediate gene transcription. Preliminary data also support the in vivo role of ARF6 in uveal melanoma. When ARF6 is silenced in uveal melanoma by shRNA or is inhibited with a small molecule inhibitor, tumor establishment and growth is significantly inhibited in an orthotopic xenograft mouse model. Based on these preliminary data, the following aims will be pursued. In Aim 1, we will investigate whether activated Gαq proteins induce ß-catenin signaling via activation of ARF6 in uveal melanoma. We will employ gene silencing via RNA interference and small molecule inhibition of selected targets to assess intracellular localization, transcriptional activity, and function of ß-catenin in uveal melanoma. In Aim 2, we will elucidate the role of ARF6 in orchestrating known downstream signaling pathways of oncogenic Gαq. The same strategies used in Aim 1 will be employed to determine whether ARF6 acts as an immediate downstream effector of activating GNAQ/GNA11 mutations to control (PLC-ß/PKC) and TRIORhoA/ Rac1 pathways and AP-1 and YAP-TEAD-mediated transcription. In Aim 3, we will assess the in vivo function of ARF6 in tumor establishment and growth by using orthotopic xenograft models of human uveal melanoma. The successful completion of these aims will allow us to determine whether ARF6 plays a critical role in Gq signaling, thus providing a promising therapeutic target for the development of drugs that could be used to treat uveal melanoma and possibly other Gαq-related disorders such as Sturge-Weber syndrome.
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