The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia
血管平滑肌细胞中 IGF-1 信号传导在年龄相关血管认知障碍和痴呆中的作用
基本信息
- 批准号:10489846
- 负责人:
- 金额:$ 35.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-30 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptionAffectAgeAge-YearsAge-associated memory impairmentAgingAlzheimer&aposs disease related dementiaApoptosisAreaBehavioralBlood VesselsBrainCell ProliferationCellsCerebrovascular DisordersCerebrovascular systemCerebrumCharacteristicsChronologyCognitiveCoupledDataDefectDevelopmentDiseaseElderlyEquilibriumEventExhibitsExtracellular MatrixFunctional disorderGait abnormalityGeneticGenetic TranscriptionGeroscienceGoalsGrowthHealthHealth Care CostsHemorrhageHomeostasisHumanHyperplasiaHypertensionHypertrophyIGF1 geneImpaired cognitionImpairmentIncidenceIndividualInflammationInflammatoryInsulin-Like Growth Factor IInsulin-Like-Growth Factor I ReceptorKnock-outLinkLocationMediatingModelingMolecular ProfilingNeuronal DysfunctionNeuronsOxidative StressPathologyPathway interactionsPhenotypePhysiologicalPlayPopulationProcessPublic HealthQuality of lifeRegulationRiskRisk FactorsRodent ModelRoleRuptureSignal TransductionSmooth Muscle MyocytesSomatomedinsStimulusStressSubgroupTestingTherapeutic InterventionVascular Cognitive ImpairmentVascular Smooth MuscleWorkage relatedagedaging braincell growthcerebral microbleedscerebrovascularcognitive developmentcohortdisabilityeffective therapyhealthspanin vivoinnovationinsightlaser capture microdissectionmicrovascular pathologymouse modelneuroinflammationnovelresponsesenescencesingle-cell RNA sequencingtherapeutic candidatevascular cognitive impairment and dementia
项目摘要
PROJECT SUMMARY/ABSTRACT
Age-related vascular cognitive impairment and dementia (VCID), a subgroup of Alzheimer’s Disease and Related
Dementias (ADRD) is a common cause of disability and reduced quality of life among the elderly. Extensive recent
data have demonstrated that microvascular pathologies in the brain play a central role in these processes. One such
pathology is cerebral microhemorrhages (CMH) which are the result of rupture of small intracerebral blood vessels
and progressively impairs neuronal function. The incidence of CMH dramatically increases with age and hypertension
is one of the major causes for age-related cognitive decline. Yet the underlying cellular mechanisms for CMH and
increased vascular fragility are unknown, and thus therapeutic interventions to mitigate CMH are not available. Blood
vessel integrity requires plasticity of vascular smooth muscle cells (VSMCs), which exhibit an adaptive switch from a
highly contractile to a protective, anti-fragility phenotype in response to stress. Aging fundamentally alters VSMC
phenotypic switching, suppressing the adoption of these protective VSMC features, which are otherwise promoted
by insulin-like growth factor (IGF)-1. Circulating IGF-1 levels are dramatically decreased with age. Low IGF-1 levels
increase the risk for cerebromicrovascular disease and promote the development of CMH in our rodent models,
supporting a role for IGF-1 deficiency in age-related vascular fragility. Our hypothesis is that impaired VSMC
plasticity and function due to IGF-1 deficiency has a fundamental role in increased cerebrovascular fragility and
development of CMH and cognitive decline with age. Aim 1 will test the hypothesis that VSMCs contribute to the
development of VCID/ADRD phenotypes in IGF-1 signaling-deficient models. We will use novel VSMC-specific IGF-
1 receptor knockout lines to probe the role of VSMCs in the development of CMH, impaired myogenic autoregulation
in response to hypertension, and the consequent development of cognitive decline. Aim 2 will determine the
dynamic balance between VSMCs with maladaptive phenotypes and VSMCs with protective phenotypes induced
by age-dependent decrease of IGF1. In this aim we will address the question of VSMC plasticity in vivo,
evaluating both protective and maladaptive VSMC phenotypes in the cerebrovasculature of Igf1r-deficient CMH
models. Aim 3 will evaluate the transcriptional mechanisms governing maladaptive and protective VSMC
phenotypes in regions of vascular fragility/CMH and in surrounding intact vessels. Lineage tracing genetic mouse
models of aging and IGF-1 deficiency, coupled with single-cell RNA-sequencing, will be used to evaluate the
role of novel transcriptional regulators in the adoption of diverse VSMC phenotypes. Pro- and anti-fragility VSMC
phenotypic states will be spatially overlaid with the location of CMH to test the hypothesis that CMH occur
primarily in regions where VSMCs show a maladaptive phenotype. These scientifically and technically innovative
studies will significantly enhance our understanding of the role of IGF-1 deficiency in the development of CMH
and will provide insight into underlying cellular mechanisms which are critical for the development of effective
therapies.
项目总结/摘要
阿尔茨海默病及其相关疾病的一个亚组,阿尔茨海默病相关的血管性认知障碍和痴呆(VCID)
痴呆症(ADRD)是老年人残疾和生活质量下降的常见原因。最近广泛
数据表明,大脑中的微血管病变在这些过程中起着中心作用。一个这样
病理学是脑微血管瘤(CMH),其是脑内小血管破裂的结果
并逐渐损害神经元功能。CMH的发病率随着年龄和高血压的增加而显著增加
是与年龄相关的认知能力下降的主要原因之一。然而,CMH的潜在细胞机制和
增加的血管脆性是未知的,因此没有缓解CMH的治疗干预。血液
血管完整性需要血管平滑肌细胞(VSMC)的可塑性,VSMC表现出从血管平滑肌细胞(VSMC)到血管平滑肌细胞(VSMC)的适应性转换。
在应激反应中高度收缩为保护性、抗脆性表型。衰老从根本上改变了VSMC
表型转换,抑制这些保护性VSMC特征的采用,这些特征在其他情况下会被促进
胰岛素样生长因子(IGF)-1。循环中的IGF-1水平随着年龄的增长而急剧下降。低IGF-1水平
在我们的啮齿动物模型中,增加微血管疾病的风险并促进CMH的发展,
支持IGF-1缺乏在与年龄相关的血管脆弱性中的作用。我们假设受损的血管平滑肌细胞
由于IGF-1缺乏而引起的可塑性和功能在脑血管脆性增加中起着重要作用,
CMH的发展和认知能力随年龄的下降。目的1将检验VSMC有助于
在IGF-1信号缺陷模型中VCID/ADRD表型的发展。我们将使用新的VSMC特异性IGF-
1受体基因敲除细胞系,以探索VSMC在CMH发展中的作用,
以及随之而来的认知能力下降。目标2将决定
具有适应不良表型的VSMCs和具有诱导的保护性表型的VSMCs之间的动态平衡
IGF 1的年龄依赖性下降。在这个目标中,我们将解决的问题,血管平滑肌细胞可塑性在体内,
评估Igf 1 r缺陷型CMH患者血管中的保护性和适应不良VSMC表型
模型目的3将评估调控适应不良和保护性VSMC的转录机制
在血管脆性/CMH区域和周围完整血管中的表型。谱系追踪遗传小鼠
衰老和IGF-1缺乏模型,加上单细胞RNA测序,将用于评估
新型转录调节因子在不同VSMC表型形成中的作用。促脆性和抗脆性VSMC
表型状态将与CMH的位置在空间上重叠,以检验CMH发生的假设
主要是在VSMC表现出适应不良表型的区域。这些科学和技术上的创新
这些研究将显著提高我们对IGF-1缺乏在CMH发展中的作用的认识
并将提供深入了解潜在的细胞机制,这是至关重要的发展有效的
治疗
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Shannon M Conley其他文献
Functional ultrasound as a quantitative approach for measuring functional hyperemia in aging models
功能性超声作为一种在衰老模型中测量功能性充血的定量方法
- DOI:
10.1016/j.neuroimage.2025.121313 - 发表时间:
2025-08-01 - 期刊:
- 影响因子:4.500
- 作者:
Jessica Pinckard;Sharon Negri;Cade A Huston;Marisa A Bickel;Michaela L Vance;Madison Milan;Clara L Hibbs;Madeline Budda;Siva Sai Chandragiri;Kaitlyn Pipkin;Stefano Tarantini;Shannon M Conley - 通讯作者:
Shannon M Conley
Shannon M Conley的其他文献
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{{ truncateString('Shannon M Conley', 18)}}的其他基金
The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia
血管平滑肌细胞中 IGF-1 信号传导在年龄相关血管认知障碍和痴呆中的作用
- 批准号:
10618333 - 财政年份:2021
- 资助金额:
$ 35.71万 - 项目类别:
The role of IGF-1 signaling in vascular smooth muscle cells in age-related vascular cognitive impairment and dementia
血管平滑肌细胞中 IGF-1 信号传导在年龄相关血管认知障碍和痴呆中的作用
- 批准号:
10300903 - 财政年份:2021
- 资助金额:
$ 35.71万 - 项目类别:
IGF-1, smooth muscle plasticity, and pathogenesis of cerebral microhemorrhages in aging
IGF-1、平滑肌可塑性与衰老脑微出血的发病机制
- 批准号:
10077915 - 财政年份:2019
- 资助金额:
$ 35.71万 - 项目类别:
The role of the photoreceptor tetraspanin Rds in outer segment morphogenesis
光感受器四跨膜蛋白 Rds 在外节形态发生中的作用
- 批准号:
7613537 - 财政年份:2009
- 资助金额:
$ 35.71万 - 项目类别:
The role of the photoreceptor tetraspanin Rds in outer segment morphogenesis
光感受器四跨膜蛋白 Rds 在外节形态发生中的作用
- 批准号:
7752541 - 财政年份:2009
- 资助金额:
$ 35.71万 - 项目类别:
The role of the photoreceptor tetraspanin Rds in outer segment morphogenesis
光感受器四跨膜蛋白 Rds 在外节形态发生中的作用
- 批准号:
8018107 - 财政年份:2009
- 资助金额:
$ 35.71万 - 项目类别:
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