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.
项目概要/摘要:
衰老相关的血管和脑血管功能障碍在许多结缔组织疾病中普遍存在。
马凡氏综合征(MFS)是最常见的单基因常染色体显性遗传性结缔组织病,
其特征在于编码Fbn 1的基因突变,没有性别或种族偏见。FBN1
蛋白质为肌肉、骨骼和血管提供结构支持,也为弹性蛋白纤维提供支架
细胞因子的作用是促进细胞成熟并结合细胞因子和防止有害的下游信号传导。MFS相关Fbn 1
突变导致危及生命的问题的风险增加,涉及血管壁的弱化
会导致扩张剥离和破裂Fbn 1基因突变对脑血管功能的影响
尽管MFS会导致神经功能缺损,包括头痛,偏头痛,
脑动脉瘤中风和注意力缺陷多动障碍细胞外基质(ECM)损伤,
血管壁变薄、变硬,血脑屏障(BBB)通透性增加,细胞因子水平升高
产生是与脑血管老化相关的标志性改变,在MFS中普遍存在。这些
在衰老和MFS中的表现是由于增加的转化生长因子-β(TGF-β)信号传导而发生的。在
在小鼠中,Fbn 1突变在6月龄(6 M)时诱导血管功能障碍。这种易于使用的模型具有
在290多项研究中使用,其中只有两项研究涉及血管,
大脑中动脉(MCA)壁/管腔肥大增加,
脉络丛中MCA、BBB通透性、TGF-β细胞因子和MMP的产生。这些结果和
来自该实验室的数据表明,在该模型中,
正常衰老但速度加快这导致了Fbn 1突变加速的假设
脑血管功能和神经行为改变中与年龄相关的损害。为了测试这一点,Fbn 1 +/-
将评价6个月的C57 BL/6小鼠以及6个月(CTRL)和12个月(WT)的C57 BL/6小鼠的脑血管变化
目的:1)检测血浆中TGF-β信号分子的表达,
和Fbn 1 +/-小鼠模型中的海马。2)评价脑血管结构和功能
Fbn 1 +/-小鼠模型。3)在Fbn 1 +/-小鼠模型中检查神经病理学形态和功能。一
强大的指导团队支持这一提议,并提供专门知识和资源。本实验数据支持
Fbn 1突变在加速脑血管衰老和神经病理学中起着关键作用,
在神经损伤(如轻度创伤性脑损伤)后出现更严重结局的脆弱性风险。
影响:这是首次研究Fbn 1突变作为加速脑血管老化的贡献者
和功能障碍,其中TGF-β信号通路可以揭示
预防和保护MFS中血管功能障碍和神经病理学的增加,类似于
结缔组织疾病和人口老龄化。
项目成果
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