F-box ubiquitin ligases destabilize neurofibromin
F-box ubiquitin ligases destabilize neurofibromin
批准号:
9767890
负责人:
David W Clapp
金额:
$34.45万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-01 至 2023-08-31
关键词:
AffectAllelesAutomobile DrivingB-LymphocytesBiochemicalBone MarrowBone Marrow TransplantationCellsChemotaxisClinicalComplexF Box DomainF-Box ProteinsFamilyGTPase-Activating ProteinsGenesGeneticGenetically Engineered MouseGenomeGenomic approachGlioblastomaGrowth FactorHematopoieticHematopoietic SystemHematopoietic stem cellsHeterogeneityHumanHuman GeneticsIndividualInflammatoryKnockout MiceLesionMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMediatingMetastatic MelanomaMorbidity - disease rateMusMutationMyeloid CellsNF1 geneNeurofibromatosesNeurofibromatosis 1Neurofibromatosis Type 1 ProteinNon-MalignantPathologicPathway interactionsPatientsPharmacological TreatmentPhase II Clinical TrialsPhenotypePhosphorylationPhosphotransferasesPlexiform NeurofibromaPre-Clinical ModelPredispositionPremalignantPreparationProcessProteinsRNA interference screenRadiation therapyRegulationResistanceSignal PathwaySignal TransductionSmall Interfering RNASpecificityStem Cell FactorSyndromeTestingTissuesTumor Suppressor GenesTumor Suppressor ProteinsUbiquitinUbiquitinationWorkcancer geneticschemotherapyclinically significantdrug discoveryfunctional genomicsin vivoinnovationinsightinterdisciplinary approachkinase inhibitormast cellmortalitymulticatalytic endopeptidase complexnovelpatient responsepreventrecruitresponsescreeningsuccesstherapeutic candidatetherapeutic targettumortumorigenesisubiquitin ligaseubiquitin-protein ligase
中文摘要
项目摘要/摘要
NF1肿瘤抑制基因突变导致神经纤维瘤病1型(NF1),这是人类最常见的
遗传性癌症易感综合征。NF1患者患有广泛的恶性和
非恶性临床表现包括丛状神经纤维瘤(PN)、复杂的癌前病变
它影响着25%-40%的NF1患者,并导致主要的终生发病率和死亡率。NF1基因编码
神经纤维素是p21ras(RAS)的GTP酶激活蛋白(GAP)。我们之前确定了一项损失
NF1(NF1+/-)单等位基因导致NF1患者(NF1+/-)和小鼠(NF1+/-)髓系细胞RAS过度激活,
这一概念被称为单倍体功能不全。我们创造了一种基因工程小鼠模型
神经纤维瘤病和证实丛状神经纤维瘤的形成需要炎性
NF1+/-骨髓的贡献。此外,我们还发现,对下游激酶通路的遗传抑制
血液系统中的神经纤维蛋白可防止肿瘤的发生。这项工作导致了有史以来第一次
在临床前模型和我们的II期临床试验中,成功地对这些肿瘤进行了药物治疗。
尽管取得了这一成功,但纠正神经纤维蛋白缺陷性组织中RAS过度激活的补充策略
由于RAS介导的信号通路的复杂性和患者反应的异质性而需要
对于这些对传统化疗和治疗完全耐药的复杂肿瘤,
放射治疗。
神经纤维蛋白被磷酸化、泛素化,并在蛋白酶体上被降解,以响应生长因子
刺激,但对这一过程的机制方面知之甚少。具体来说,泛素连接酶
控制肿瘤驱动的造血细胞中神经纤维蛋白降解的特异性因子(S)(E3)不是
为人所知。F-box泛素连接酶以磷酸化依赖的方式降解选定的蛋白质,导致
我们假设NF1 E3属于F-box家族。在最初的未发表的研究中,
为准备这一应用,我们进行了RNAi筛选,确定了强大的新候选F-box
NF1的泛素连接酶。在这里,我们建议对这些新发现的F-box蛋白进行机械检测
调节神经纤维素的体内外降解。我们还建议采用无偏见的功能
利用基因组学策略研究通过F盒促进神经纤维蛋白F-box降解的激酶(S)
泛素-蛋白酶体途径。我们将采用多学科方法来确定中断是否
我们的候选神经纤维蛋白E3在体内可以拯救神经纤维蛋白单倍体功能不全和预防丛状
神经纤维瘤的发生和发展。这些研究还将为监管一种
常见但未被充分研究的肿瘤抑制基因。
英文摘要
PROJECT SUMMARY / ABSTRACT
Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), the most common human
genetic cancer predisposition syndrome. Individuals with NF1 suffer from a wide range of malignant and
nonmalignant clinical manifestations including plexiform neurofibromas (PN), complex precancerous lesions
which affect 25-40% of NF1 patients and cause major lifelong morbidity and mortality. The NF1 gene encodes
neurofibromin, a GTPase-activating protein (GAP) for p21ras (Ras). We previously determined that loss of a
single allele of Nf1 (Nf1+/-) results in Ras hyperactivation in NF1 patient (NF1+/-) and murine (Nf1+/-) myeloid cells,
a concept known as haploinsufficiency. We generated a genetically engineered murine model of
neurofibromatosis and demonstrated that plexiform neurofibroma formation requires the inflammatory
contribution of Nf1+/- bone marrow. Further, we showed that genetic inhibition of kinase pathways downstream
of neurofibromin in the hematopoietic system prevents tumorigenesis. This work has led to the first ever
successful pharmacological treatment of these tumors in both preclinical models and in our phase II clinical trial.
Despite this success, complementary strategies to correct Ras hyperactivation in neurofibromin-deficient tissues
are needed due to the complexity of Ras-mediated signaling pathways and the heterogeneity of patient response
to kinase inhibitors for these complex tumors that are completely resistant to traditional chemotherapy and
radiation treatment.
Neurofibromin is phosphorylated, ubiquitinated, and degraded at the proteasome in response to growth factor
stimulation, but little is known about the mechanistic aspects of this process. Specifically, the ubiquitin ligase
specificity factor(s) (E3) that govern neurofibromin degradation in the tumor-driving hematopoietic cells are not
known. The F-box ubiquitin ligases degrade selected proteins in a phosphorylation-dependent manner, leading
us to hypothesize that the NF1 E3 belongs to the F-box family. In initial unpublished studies pursued in
preparation for this application, we conducted an RNAi screen, which identified strong novel candidate F-box
ubiquitin ligases for NF1. Here, we propose to mechanistically examine these newly identified F-box proteins
modulating neurofibromin degradation ex vivo and in vivo. We also propose to employ an unbiased functional
genomics strategy to identify kinase(s) that promote F-box-dependent degradation of neurofibromin via the
ubiquitin-proteasome pathway. We will employ a multidisciplinary approach to determine whether disruption of
our candidate neurofibromin E3s in vivo can rescue neurofibromin haploinsufficiency and prevent plexiform
neurofibroma initiation and progression. These studies will also provide basic insights into the regulation of a
common but understudied tumor suppressor gene.
期刊论文(0)
专著(0)
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会议论文
TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors
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批准号:10741104
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财政年份:2023
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依托单位:
Preclinical-clinical trials collaboration to effectively advance new combination therapies for atypical neurofibroma in neurofibromatosis type 1
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Pediatric and Adult Translational Cancer Drug Discovery and Development Training Program (PACT-D3)
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批准号:10708526
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Indiana Pediatric Scientist Award (IPSA)
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批准号:10598852
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资助金额:$32.4万
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财政年份:2023
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TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors
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依托单位:
The Medical Physician Engineers, Scientists, and Clinicians Preparatory Program [MPESC-Prep]
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批准号:10618993
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项目类别:
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资助金额:$16.03万
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财政年份:2022
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TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors
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批准号:10913886
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TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors
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批准号:10616770
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Mitotic failure in Fanconi anemia: mechanisms and role in carcinogenesis
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资助金额:$4.66万
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依托单位:
F-box ubiquitin ligases destabilize neurofibromin
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批准号:10249088
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资助金额:$34.45万
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财政年份:2018
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依托单位:
F-box ubiquitin ligases destabilize neurofibromin
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批准号:10011888
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资助金额:$34.45万
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Developmental and Hyperactive Ras Tumor (DHART) SPORE
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资助金额:$213.95万
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负责人:David W Clapp
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依托单位:
FRONTIERS IN SCIENCE CONFERENCE
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资助金额:$1.0万
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依托单位:
FRONTIERS IN SCIENCE CONFERENCE
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资助金额:$0.6万
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依托单位:
PROJECT 1: From Neurofibroma to MPNST: Models, Biology and Translation to Clinic
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资助金额:$57.08万
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依托单位:
FRONTIERS IN SCIENCE CONFERENCE
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资助金额:$1.0万
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依托单位:
Developmental and HyperActive Ras Tumor SPORE
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批准号:9341155
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负责人:David W Clapp
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依托单位:
Administrative Core
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批准号:10270578
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负责人:David W Clapp
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依托单位:
Project 1: Molecular and Genetic Features Across Mouse and Human Plexiform Neurofibromas to Inform Clinical Trials
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批准号:8932162
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资助金额:$12.38万
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依托单位:
FRONTIERS IN SCIENCE CONFERENCE
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资助金额:$1.0万
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依托单位:
海外基金