Activation of transposable elements as an endogenous source of neoepitopes and mediators of tumor immunogenicity
Activation of transposable elements as an endogenous source of neoepitopes and mediators of tumor immunogenicity
批准号:
10531992
负责人:
Aguirre A de Cubas
金额:
$12.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-05-01 至 2025-04-30
关键词:
Antigen PresentationAntiviral ResponseBioinformaticsCTLA4 geneCaliberCell LineCell physiologyClear cell renal cell carcinomaClinicalClinical TrialsComputational BiologyDNADNA Transposable ElementsDataDevelopmentDiseaseDoctor of PhilosophyEducational workshopElementsEndogenous RetrovirusesEpigenetic ProcessEventFacultyFluorescence MicroscopyFutureGenetic TranscriptionGenomicsGoalsGrantImmune responseImmune systemImmunityImmunologicsImmunologyImmunooncologyImmunoprecipitationImmunosuppressionImmunotherapyImpotenceInstitutionInterferonsInvestigationLaboratoriesLaboratory PersonnelLibrariesMalignant NeoplasmsMass Spectrum AnalysisMediatingMediator of activation proteinMentored Research Scientist Development AwardMentorsMentorshipMessenger RNAOpen Reading FramesPathogenicityPathway interactionsPatientsPeptidesPersonnel ManagementPharmaceutical PreparationsPharmacotherapyPhasePheochromocytomaPositioning AttributeProcessProductionPrognosisProteinsProteomicsRNARNA SplicingRegulationRelapseRenal Cell CarcinomaRenal carcinomaReporterReportingRepressionResearchResearch PersonnelResearch TrainingResponse ElementsRoleSignal TransductionSourceT-LymphocyteTBK1 geneTestingTherapeuticTimeTrainingTraining ActivityTranscriptTranscription Initiation SiteTranslatingTumor-infiltrating immune cellsUniversitiesViralanti-CTLA4anti-PD-L1anti-canceranticancer researchbasecancer therapycareercareer developmentchromatin immunoprecipitationclinical applicationdesignepigenetic therapyevidence baseexperiencegenomic datahigh throughput screeningimmune activationimmune checkpoint blockadeimmune clearanceimmunogenicimmunogenicityin vivo Modelinnovationinsightknock-downmemberneoantigensnew therapeutic targetnext generation sequencingnovelnovel therapeutic interventionnovel therapeuticsoutcome predictionpathogenpatient populationpredicting responseprotein aminoacid sequencereceptorresearch studyresponsesuccesstenure tracktranslational cancer researchtumortumor immunologytumor microenvironmenttumor-immune system interactionsurologic
中文摘要
1 .项目摘要/摘要
英文摘要
1 PROJECT SUMMARY/ABSTRACT
2 Candidate Background: I received my Ph.D. from the Autonomous University of Madrid with Dr. Mercedes Robledo,
3 focusing on genomic characterization of pheochromocytoma. My postdoctoral research studies with Dr. WK Rathmell at
4 Vanderbilt University with a focus epigenetic factors in the development and progression of renal cancer.
5 Career Goals and Objectives: My career goal is to become an independent, tenure-track faculty member at a high-caliber
6 research institution, working with an interdisciplinary team, and focusing on identifying new therapies for kidney cancer.
7 Career Development and Training Activities: My training plan revolves around mentorship, didactic training, and
8 protected research time to support my transition to independence. Dr. WK Rathmell will serve as my primary mentor; she
9 will train me in laboratory and personnel management, grant administration, and translational kidney cancer research. Dr.
10 Jeff Rathmell will provide mentorship in tumor microenvironment, and Dr. Gyan Bhanot will provide mentorship in
11 computational biology. I will attend selected seminars and workshops, and continue responsible conduct in research training.
12 Significance and Innovation: Although immune checkpoint blockade (ICB) has shown remarkable success in treating
13 metastatic kidney cancer (RCC), not all patients respond to therapy. We recently reported that high expression of
14 endogenous retroviruses, a class of transposable element (TE), occurs in a subset of RCC tumors and can predict response
15 to ICB in RCC. Mobile genomic elements, TEs are usually suppressed by a number of epigenetic mechanisms. Aberrant
16 expression of TEs can activate host antiviral responses and produce neoantigens, and in some RCCs, activate antiviral response
17 that results in increased immunogenicity, characterized by increased immune infiltrate. Thus, it is our premise that epigenetic
18 modulation of TE expression represents a novel therapeutic strategy to enhance response to ICB in RCC and other cancers.
19 Approach: Based evidence to date, I hypothesize 1) that epigenetic activation of TEs enhances neoantigen production to
20 contribute to immunogenicity in RCC, and 2) that additional epigenetic mechanisms exist that regulate TE activity and that
21 these can be manipulated to promote immunogenicity.
22 Specific Aim 1: Define the role that epigenetic activation of transposable elements has in neoepitope production. 1A)
23 Interrogate transcriptional landscapes associated with epigenetic activation of TEs. 1B) Identify naturally processed TE-
24 associated neoepitopes.
25 Specific Aim 2: Define additional epigenetic mechanisms governing TE expression. 2A) Define epigenetic mechanisms
26 mediating TE suppression. 2B) Determine how epigenetic activation of TEs mediate host antiviral response. 2C) Elucidate
27 mechanisms behind TE-induced IFN signaling.
28 Transition to Independence: I will apply to faculty positions during the Mentored phase and accepting a tenure track
29 position to transition to the Independent phase. My goal is to characterize novel mechanisms for TE-associated antitumor
30 immunity and identify novel targets regulating TEs. These studies will serve as the basis for an NCI R01 application.
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Activation of transposable elements as an endogenous source of neoepitopes and mediators of tumor immunogenicity
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批准号:10663369
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项目类别:
-
资助金额:$11.98万
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财政年份:2020
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负责人:Aguirre A de Cubas
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依托单位:
海外基金