Decoding the Molecular and Cellular Mechanisms of Mutant KRAS-driven Brain Arteriovenous Malformations
解读突变 KRAS 驱动的脑动静脉畸形的分子和细胞机制
基本信息
- 批准号:10446836
- 负责人:
- 金额:$ 67.2万
- 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:AdultAffectAnatomyAngiogenic FactorAnimal Disease ModelsAnimal ModelArteriesBehavioral AssayBiologyBlood VesselsBlood capillariesBlood flowBrain NeoplasmsBrain hemorrhageCaliberCell Culture TechniquesCell ShapeCellsCellular MorphologyCellular biologyCerebral cortexCessation of lifeChildClinicalCognitionCognitiveCuesCultured CellsCytoskeletonDataDevelopmentDiagnosisDiseaseDown-RegulationEndothelial CellsEndotheliumEtiologyEventExtracellular MatrixFDA approvedFamily history ofFrequenciesGTP BindingGene ExpressionGene Expression ProfilingGenesGeneticGenetic TranscriptionGoalsGuanosine Triphosphate PhosphohydrolasesHemorrhageHistologicHistologyHomeostasisHumanHypertensionHypoxiaImageImmunohistochemistryIn VitroInterventionKRAS2 geneKnowledgeLabelLesionMEK inhibitionMEKsMaintenanceMedicalMinorityMitogen-Activated Protein KinasesModalityModelingMolecularMolecular TargetMonomeric GTP-Binding ProteinsMorbidity - disease rateMosaicismMovementMusMutationNeuraxisNeurofibrillary TanglesOperative Surgical ProceduresPathogenesisPathologicPathway interactionsPatient-Focused OutcomesPatientsPericytesPharmaceutical PreparationsPharmacologyPhenotypePre-Clinical ModelProcessPublishingRadiationResistanceRiskRuptureSamplingSeverity of illnessShunt DeviceSignal TransductionSmooth Muscle MyocytesStressStrokeTestingTherapeutic EmbolizationTimeVascular Smooth MuscleVascular remodelingVeinsZebrafishbrain arteriovenous malformationscadherin 5cell behaviordesigndisability riskexome sequencingfeedingfunctional disabilityhemodynamicshigh riskimprovedin vivoinhibitorinsightmalformationmutantneuron lossnovelnovel therapeuticsoptogeneticspreventrecruitresponsesensorshear stresssingle-cell RNA sequencingsurgical risktherapeutic targettranscriptomicsvascular bedyoung adult
项目摘要
SUMMARY
Brain arteriovenous malformations (bAVMs) are composed of abnormal connections between arteries and veins
that lack an intervening capillary network. As a result, high-pressure blood from feeding arteries shunts directly
into veins. These vascular lesions become distended and highly remodeled, resulting in a tangle of enlarged
blood vessels that are prone to rupture. Indeed, bAVMs are a leading cause of hemorrhagic stroke in children
and young adults. All current treatment modalities for bAVMs, including surgery, embolization or radiation carry
a significant risk of disability or death, and these options are not available for ~20% of bAVM patients due to
excessive risk. Because of these complications, alternative medical strategies with lower morbidities such as
targeted pharmacological therapies are desperately needed. However, we first need a clear understanding of
the biology underlying bAVM development and maintenance. The majority of bAVMs occur sporadically without
a family history of the disease. Using whole exome sequencing, we recently identified somatic, activating
mutations in the KRAS gene, which encodes a GTPase that is involved in signal transduction. The identified
mutations were confined to the endothelium and result in KRAS being locked in a GTP-bound ‘ON’ state. Notably,
we have established mouse and zebrafish models of endothelial-specific expression of mutant KRAS, which
have revealed the sufficiency for these genetic lesions to drive disease. We have gone on to demonstrate,
through transcriptional profiling of cultured cells and in vivo studies in zebrafish expressing mutant KRAS, that
many KRAS-induced molecular and cellular changes require MEK/ERK activity. Much remains to be learned
regarding the etiology of sporadic bAVMs and our cell culture, mouse and zebrafish models will enable us to
define the molecular, cellular and morphological changes that are involved in the initiation and maintenance of
bAVMs. We will utilize our expertise in animal models of bAVMs, imaging, cell biology, signaling and single-cell
RNA sequencing, to gain unprecedented insight into the bAVM disease process. This information will be
leveraged for the design of pharmacological interventions to improve patient outcomes. Our proposal will: 1)
define the threshold of KRAS mutant endothelial cells that can remodel vessels, 2) identify the vascular bed(s)
that are susceptible to active KRAS expression, 3) determine how KRAS mutations impact hemodynamic
signaling and bAVM progression, 4) uncover the cell-autonomous and non-cell autonomous mechanisms of
mutant KRAS, and 4) determine the requirement for KRAS and MEK activation for bAVM maintenance in our
pre-clinical models. Together, these studies will expand our understanding of bAVM pathogenesis and will
assess whether inhibition of the KRAS/MEK pathway may be a viable therapeutic target to pursue in human
patients with bAVM.
总结
项目成果
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Jason Fish其他文献
Jason Fish的其他文献
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{{ truncateString('Jason Fish', 18)}}的其他基金
Decoding the Molecular and Cellular Mechanisms of Mutant KRAS-driven Brain Arteriovenous Malformations
解读突变 KRAS 驱动的脑动静脉畸形的分子和细胞机制
- 批准号:
10584546 - 财政年份:2022
- 资助金额:
$ 67.2万 - 项目类别:
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