BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Role of PPARg in theFormation and Progression of Carcinoma in situ of the Bladder
BCCMA:暴露于致癌物的退伍军人尿路上皮癌症发生的基本和转化机制:PPARg 在膀胱原位癌形成和进展中的作用
基本信息
- 批准号:10361590
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAnimal ModelAreaArtificial IntelligenceAttentionAutomobile DrivingBasic ScienceBehaviorBiologicalBiological MarkersBladderBladder mucosaCDH1 geneCarcinogensCarcinoma in SituCellsClinicalClinical ResearchCytogenetic AnalysisDataDetectionDiagnosisDifferentiation AntigensDifferentiation and GrowthDominant-Negative MutationDoxycyclineEZH2 geneEarly DiagnosisEmotionalEnvironmentEpigenetic ProcessEpithelialExhibitsExposure toGTP-Binding Protein alpha Subunits, GsGeneticGenetic DriftGenetic TranscriptionGenetically Engineered MouseGenomicsHeterogeneityHumanImmuneImmunotherapeutic agentImmunotherapyIn Situ LesionInfiltrationKDM1A geneKnock-outKnowledgeLesionLocal TherapyMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of urinary bladderMedicalMedical centerModelingMolecularMonitorMuscleNeoplasm MetastasisOccupationsOncogenicOrganPPAR gammaPainPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPhenotypePhysiologicalPolycombPreventionQuality of lifeRadical CystectomyRadioReagentRecurrenceRepressor ProteinsResearch ProposalsResourcesRiskRoleScientistSeriesSmokingSquamous cell carcinomaSystemTP53 geneTamoxifenTestingTobacco smokeTranscriptional RegulationTranslational ResearchTreatment EfficacyTumor-infiltrating immune cellsUPK2 geneUrothelial CellUrotheliumVariantVeteransbasebiomarker-drivenbladder carcinoma in situcancer initiationchemical carcinogenesiscostdesigneffective therapyexperienceexperimental studygenetic analysisimmunological statusimprovedin vivoinsightintravesicallost work timemolecular subtypesmuscle invasive bladder cancermutantnew therapeutic targetnovelnovel diagnosticspremalignantpreventprogramsresponserisk predictionrisk stratificationsingle-cell RNA sequencingsynergismtherapeutic targettranscription factortreatment response
项目摘要
Project Summary Abstract
BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans
Exposed to Carcinogens: CMA2: Role of PPAR- in the Formation and Progression of Carcinoma in
situ of the Bladder
Although bladder cancer (BC) ranks the fourth among the most prevalent cancers in the Veterans, it has
received a level of attention far less than many other prevalent cancers in basic, translational and clinical
research. Carcinoma in situ (CIS) of the bladder is a precancerous lesion, believed to be caused by specific
carcinogens in tobacco smoke, occupation and environment, has a high rate of recurrence and progression to
invasion and metastasis. Despite its critical importance, major knowledge gaps exist regarding the genomic,
epigenetic and transcriptional underpinning of CIS, leading to unmet challenges in early detection, accurate
prediction of progression and prevention. Two basic scientists and two clinicians from four VA Medical Centers
have joined forces to tackle the molecular mechanisms of CIS formation and progression in an interdisciplinary
and collaborative manner by sharing ideas, reagents and resources. CMA1 will focus on the mechanistic
bases of human CIS regulated by EZH2 and the polycomb repressor complex 2 (PRC2). CMA2 aims to
understand the transcriptional controls, especially PPAR-γ, whereby CIS forms and progresses to muscle
invasion. CMA3 will use epigenetic approaches to prevent or delay smoking-related BC by targeting lysine-
specific demethylase 1. CMA4 will develop a biomarker-driven, artificial intelligence-enhanced cystoscopic
strategy to detect CIS and assess treatment response. Extensive crosstalk and interactions have been put in
place in each CMA to enhance the synergy and efficiency of the entire program. Together, this collaborative
project should significantly advance our understanding of the genetic and epigenetic bases of CIS, yielding
novel diagnostic and therapeutic targets for its sensitive detection, effective treatment and early prevention.
Rationale: While there is a clear need for us to better understand the fundamental mechanisms underlying
how BC initiates and progresses, efforts in this area remain grossly inadequate. Bladder is an easily accessible
organ, and lesions suspected of any malignant potential can theoretically be detected early and monitored
effectively. A typical example is the CIS lesion, a precancerous entity of the bladder mucosa lining that is highly
recurrent and frequently advances to muscle invasion despite constant surveillance and local therapies.
Accumulating evidence suggests that CIS is highly heterogeneous, exhibiting diverse biological behaviors and
risks of progression. However, no reliable biomarkers exist to differentiate the genetic or molecular variants
within CIS. In this application, we have devised a series of physiologically relevant, in vivo experiments to
examine whether alternations in specific transcription factors that control normal bladder epithelial growth and
differentiation affect the formation and progression of CIS into different subtypes of muscle-invasive bladder
cancer. We will also assess how biologically different CIS lesions have differed immune status and how that
information can be explored to improve responses to local immunotherapeutics.
Clinical implications: We expect our proposed studies to offer new insights into the molecular bases
underlying the heterogeneity of CIS and the relationship between CIS lesions and the molecular subtypes of
muscle-invasive bladder cancer. Our studies should yield biologically validated and mechanistically based
biomarker sets that can potentially be used clinically for early CIS detection, risk stratification and prediction of
progression. Our studies should also identify new molecules that are proven critical for CIS formation and
progression for therapeutic targeting.
项目摘要
项目成果
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{{ truncateString('XUE-RU WU', 18)}}的其他基金
BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Role of PPARg in theFormation and Progression of Carcinoma in situ of the Bladder
BCCMA:暴露于致癌物的退伍军人尿路上皮癌症发生的基本和转化机制:PPARg 在膀胱原位癌形成和进展中的作用
- 批准号:
10616472 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Role of Tamm-Horsfall Protein in Urinary Tract Defense
Tamm-Horsfall 蛋白在尿路防御中的作用
- 批准号:
8785878 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Molecular and Genetic Studies of Bladder Tumorigenesis
膀胱肿瘤发生的分子和遗传学研究
- 批准号:
10427138 - 财政年份:2013
- 资助金额:
-- - 项目类别:
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