Identification and Characterization of a Endogenous EGFR Regulatory Locus in Xiphophorus Genome
剑尾鱼基因组中内源 EGFR 调节位点的鉴定和表征
基本信息
- 批准号:10296895
- 负责人:
- 金额:$ 45.14万
- 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:2021-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Automobile DrivingBackcrossingsBenignBiological ModelsBook ChaptersCancer Cell GrowthCancer EtiologyCandidate Disease GeneCell DeathCell ProliferationCell SurvivalCetuximabChromosome 5Chromosome MappingCodeDevelopmentDoctor of PhilosophyEGFR Protein OverexpressionEGFR geneElementsEnrollmentEpidermal Growth Factor ReceptorExhibitsFc ReceptorFishesGenesGenetic ModelsGenomeGoalsHumanHybridsImpairmentInterviewJournalsKnock-outKnowledgeLeadLigand BindingMalignant NeoplasmsMedicineMembraneMethodsMolecularMolecular TargetMonoclonal AntibodiesMusMutationNamesOncogenesOncogenicOryziinaePathway interactionsPatientsPeer ReviewPenetrancePharmaceutical PreparationsPhenotypePhosphotransferasesPlatyfishPublishingReceptor Protein-Tyrosine KinasesRegulationRegulator GenesRelapseResearchResistanceResistance developmentSignal PathwaySignal TransductionStudentsTherapeuticTransgenic OrganismsTyrosine Kinase InhibitorUniversitiesXiphophoruscancer cellcancer therapycancer typecarcinogenesiscell typeclinical applicationdesigndimerdisorder controlgenetic analysisgenetic elementgenomic locusinhibitor/antagonistmelanomagenesismutantnext generationnovelnovel therapeutic interventionoverexpressionpostersprogramsresponsesegregationsmall moleculetreatment strategytumortumorigenesis
项目摘要
Project Summary:
The epidermal growth factor receptor (EGFR) is a leading oncogene firmly
associated with many types of cancer. Both anti-EGFR small molecules and
monoclonal antibodies have been developed to block its kinase activity for cancer
treatment. However, innate and acquired resistance are frequently observed in
clinical application. Such observations significantly limit anti-EGFR medicines
usage, and also challenge current knowledge of EGFR-driver cancer. Therefore,
it is necessary to study the relationship between EGFR and cancer from a
different angle, with different research strategy.
Xiphophorus maculatus encodes a mutant, autonomous, dysregulated and
oncogenic EGFR, named xmrk. However, carcinogenesis is only observed in
backcross interspecies hybrid between xmrk positive and xmrk-null Xiphophorus
species, or when xmrk is ectopically expressed in non-Xiphophorus model system
(e.g., medaka, murine). These suggest that X. maculatus genome also encode a
regulator gene that may co-evolved with xmrk and is able to suppressing its
oncogenic activity. Therefore, characterizing how the regulator, termed R(Diff)
inhibit xmrk, may lead to novel therapeutic strategy in controlling EGFR.
Our recent study has defined the R(Diff) tumor regulatory locus to a 101.7 kbp
locus on chromosome 5. This small candidate size and low candidate gene
number enables functional and mechanistic studies are impractical. Therefore,
this proposal is designed to final determine the R(Diff) locus by examining the
following aims:
Aim 1: We will characterize all expressed but unannotated genetic elements, in
addition to the known coding genes, within the newly identified candidate R(Diff)
locus, to fully annotate the R(Diff) locus.
Aim 2: We will determine the gene/element(s) carrying R(Diff) activity by
performing gene knock-out in non-tumor-bearing Xiphophorus fish, tumor-bearing
hybrids, and tumor-bearing transgenic medaka.
Aim 3: We will profile xmrk and R(Diff) candidates, as well as phenotypes of
several Xiphophorus hybrids, to define R(Diff) by association of candidate
sequence with varied phenotypes.
项目概要:
表皮生长因子受体(EGFR)是一种重要的癌基因,
与多种癌症有关。抗EGFR小分子和
已经开发出单克隆抗体来阻断其激酶活性,
治疗然而,先天性和获得性抗性经常在
临床应用这些观察结果显著限制了抗EGFR药物
使用,也挑战了EGFR驱动癌症的现有知识。因此,我们认为,
有必要从多个角度研究EGFR与肿瘤的关系,
不同的研究视角,不同的研究策略。
斑剑尾鱼编码一种突变的,自主的,失调的,
致癌EGFR,命名为xmrk。然而,致癌作用仅在
Xmrk阳性与Xmrk阴性剑尾鱼种间杂种回交
种,或者当xmrk在非剑尾鱼模型系统中异位表达时
(e.g.,青鳉,鼠)。这表明X. maculatus基因组还编码一种
调节基因,可能与xmrk共同进化,并能够抑制其
致癌活性因此,描述调节器,称为R(Diff)
抑制xmrk可能导致控制EGFR新的治疗策略。
我们最近的研究已经将R(Diff)肿瘤调节位点确定为101.7 kbp,
位于5号染色体上。这种小的候选大小和低的候选基因
数字使功能和机制的研究是不切实际的。因此,我们认为,
该建议旨在通过检查
以下目标:
目标1:我们将描述所有表达但未注释的遗传元件,
除了已知的编码基因,在新确定的候选R(Diff)
轨迹,以完全注释R(Diff)轨迹。
目的2:我们将通过以下方法确定携带R(Diff)活性的基因/元件:
在非荷瘤剑尾鱼中进行基因敲除,
杂种和携带肿瘤的转基因青鳉。
目标3:我们将分析xmrk和R(Diff)候选者,以及
几个剑尾鱼杂种,通过候选者的关联来定义R(Diff)
具有不同表型的序列。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Global assessment of organ specific basal gene expression over a diurnal cycle with analyses of gene copies exhibiting cyclic expression patterns.
- DOI:10.1186/s12864-020-07202-9
- 发表时间:2020-11-11
- 期刊:
- 影响因子:4.4
- 作者:Lu Y;Boswell M;Boswell W;Salinas RY;Savage M;Reyes J;Walter S;Marks R;Gonzalez T;Medrano G;Warren WC;Schartl M;Walter RB
- 通讯作者:Walter RB
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{{ truncateString('Yuan Lu', 18)}}的其他基金
Real-world Evidence to Inform Decisions for Hypertension Treatment Escalation
真实世界证据为高血压治疗升级决策提供信息
- 批准号:
10718670 - 财政年份:2023
- 资助金额:
$ 45.14万 - 项目类别:
Advancement of the Xiphophorus Model for Studying Disease
研究疾病的剑尾动物模型的进展
- 批准号:
10805701 - 财政年份:2023
- 资助金额:
$ 45.14万 - 项目类别: