Accelerated Cerebrovascular Aging in a Fibrillin-1 Mutated Mouse Model
Fibrillin-1 突变小鼠模型加速脑血管老化
基本信息
- 批准号:10727231
- 负责人:
- 金额:$ 5.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAddressAgeAge MonthsAgingAneurysmAortaArteriesAttention deficit hyperactivity disorderAttenuatedBehaviorBindingBiologicalBiological AssayBlood - brain barrier anatomyBlood VesselsBlood capillariesBrainBrain regionBreedingC57BL/6 MouseCerebral AneurysmCerebrovascular CirculationCerebrovascular DisordersCerebrovascular systemConnective Tissue DiseasesDataDiseaseDissectionElasticityElastinElastin FiberEndotheliumExtracellular MatrixExtravasationFBN1FemaleFrequenciesFunctional disorderGenesGeneticGlutamatesGoalsHeadacheHeritabilityHippocampusHypertrophyImmunohistochemistryImpairmentIncidenceIndividualInduced MutationInflammationInflammatoryInvestigationKineticsKnowledgeLifeLocationMMP2 geneMMP9 geneMarfan SyndromeMatrix MetalloproteinasesMeasuresMediatingMentorsMicroelectrodesMicrogliaMigraineModelingMolecularMorphologyMusMuscleMutateMutationNeurologicNeurologic DeficitOutcomePathway interactionsPatientsPeripheralPlasmaPlayPreventionProductionProteinsPublic HealthPublicationsQuality of lifeRandomizedRattusRegional PerfusionReportingResearchResourcesRiskRisk FactorsRoleRuptureSeveritiesSex BiasSex DifferencesSignal PathwaySignal TransductionSignaling MoleculeStrokeStructureStructure of choroid plexusStructure of posterior cerebral arteryTGFB1 geneTestingTransforming Growth Factor betaUltrasonographyVascular DiseasesWild Type Mouseagedaging populationarterial stiffnessautosomebiological sexblood-brain barrier permeabilizationbonecerebrovascularcerebrovascular pathologycomparison controlcytokinedementia riskendothelial dysfunctionethnic biasexperimental studyfluid percussion injuryglial activationhigh riskimprovedin vivoinflammatory markerinterestmalemiddle cerebral arterymild traumatic brain injurymouse modelneurobehavioralneuropathologyneurotransmissionnew therapeutic targetnormal agingnovelpatient populationpersonalized medicinepre-clinicalpreservationpreventscaffoldsextherapeutic targetvascular cognitive impairment and dementia
项目摘要
Project Summary/Abstract:
Aging-associated vascular and cerebrovascular dysfunction is prevalent in many connective tissue disorders.
Marfan syndrome (MFS) is the most common monogenetic autosomal dominant disorder of connective tissue,
characterized by mutations in the gene encoding for fibrillin-1 (Fbn1), with no gender or ethnic bias. Fbn1
protein provides structural support for muscles, bones, and blood vessels as well as a scaffold for elastin fiber
maturation and to bind cytokines and prevent deleterious downstream signaling. MFS-associated Fbn1
mutation results in an increased risk of life-threatening problems involved in weakening of blood vessel walls
that can lead to dilation, dissection, and rupture. The role of Fbn1 mutation on cerebrovascular function has
barely begun to be addressed though MFS causes neurological deficits including headaches, migraines,
cerebral aneurysms, stroke, and attention deficit hyperactivity disorder. Extracellular matrix (ECM) impairment,
vascular wall weakening, and stiffening, blood brain barrier (BBB) permeability, and exacerbated cytokine
production are hallmark alterations associated with cerebrovascular aging and are prevalent in MFS. These
manifestations in aging and MFS occur due to increased transforming growth factor-beta (TGF-β) signaling. In
mice, Fbn1 mutation induces vascular dysfunction by 6-month (6M) of age. This readily accessible model has
been used in more than 290 studies, where only two have addressed the cerebrovasculature, demonstrating
increased middle cerebral artery (MCA) wall/lumen hypertrophy, matrix metalloproteinases (MMPs) in the
MCA, BBB permeability, and TGF-β cytokine and MMP production in the choroid plexus. These results and
data from this lab suggest that increased cerebrovascular aging is occurring in this model similar to that of
normal aging, but with an accelerated pace. This has led to the hypothesis that Fbn1 mutation accelerates
aging-associated compromise in cerebrovascular function and neurobehavioral alterations. To test this, Fbn1+/-
mice at 6M, and C57BL/6 mice at 6 (CTRL) and 12M (WT) will be evaluated for cerebrovascular alterations
and neuropathology through these Aims: 1) measure the expression of TGF-β signaling molecules in plasma
and the hippocampus in an Fbn1+/- mouse model. 2) evaluate cerebrovascular structure and function in an
Fbn1+/- mouse model. 3) examine neuropathological morphology and function in an Fbn1+/- mouse model. A
strong mentoring team supports this proposal and provides expertise and resources. Data from this lab support
that Fbn1 mutation plays a critical role in accelerated cerebrovascular aging and neuropathology that increases
the risk of vulnerability for more severe outcomes after neurological insult such as mild traumatic brain injury.
Impact: This is the first investigation of Fbn1 mutation as a contributor to accelerated cerebrovascular aging
and dysfunction, where the TGF-β signaling pathway may reveal mechanisms and therapeutic targets for
prevention and protection against increasing vascular dysfunction and neuropathology in MFS, similar
connective tissue disorders, and the aging population.
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