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/文摘
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
WELL-CALF: optimising accuracy for commercial adoption
WELL-CALF:优化商业采用的准确性
- 批准号:
10093543 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Collaborative R&D
Investigating the Adoption, Actual Usage, and Outcomes of Enterprise Collaboration Systems in Remote Work Settings.
调查远程工作环境中企业协作系统的采用、实际使用和结果。
- 批准号:
24K16436 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
EU-Funded
Assessing the Coordination of Electric Vehicle Adoption on Urban Energy Transition: A Geospatial Machine Learning Framework
评估电动汽车采用对城市能源转型的协调:地理空间机器学习框架
- 批准号:
24K20973 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 35.71万 - 项目类别:
EU-Funded
Our focus for this project is accelerating the development and adoption of resource efficient solutions like fashion rental through technological advancement, addressing longer in use and reuse
我们该项目的重点是通过技术进步加快时装租赁等资源高效解决方案的开发和采用,解决更长的使用和重复使用问题
- 批准号:
10075502 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Grant for R&D
Engage2innovate – Enhancing security solution design, adoption and impact through effective engagement and social innovation (E2i)
Engage2innovate — 通过有效参与和社会创新增强安全解决方案的设计、采用和影响 (E2i)
- 批准号:
10089082 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
EU-Funded
De-Adoption Beta-Blockers in patients with stable ischemic heart disease without REduced LV ejection fraction, ongoing Ischemia, or Arrhythmias: a randomized Trial with blinded Endpoints (ABbreviate)
在没有左心室射血分数降低、持续性缺血或心律失常的稳定型缺血性心脏病患者中停用β受体阻滞剂:一项盲法终点随机试验(ABbreviate)
- 批准号:
481560 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Operating Grants
Collaborative Research: SCIPE: CyberInfrastructure Professionals InnoVating and brOadening the adoption of advanced Technologies (CI PIVOT)
合作研究:SCIPE:网络基础设施专业人员创新和扩大先进技术的采用 (CI PIVOT)
- 批准号:
2321091 - 财政年份:2023
- 资助金额:
$ 35.71万 - 项目类别:
Standard Grant