Targeting Kruppel-like Transcription Factor for White and Grey Matter Protection in Vascular Cognitive Impairment and Dementia
针对血管认知障碍和痴呆症中白质和灰质保护的 Kruppel 样转录因子
基本信息
- 批准号:10625096
- 负责人:
- 金额:$ 60.95万
- 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:2023-07-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAttenuatedBinding SitesBlood - brain barrier anatomyBlood PreservationBlood VesselsBrainBrain InjuriesCardiovascular systemCellsCerebrovascular CirculationCerebrovascular DisordersCerebrovascular TraumaCerebrovascular systemCerebrumChronicCognition DisordersCognitiveDementiaDevelopmentDiabetes MellitusDifferentiation and GrowthDiffuseEconomicsEndotheliumExtravasationFamilyFamily memberGeneticImmuneImpaired cognitionInflammationInflammatory ResponseInjuryIntravenousInvestigationKruppel-like transcription factorsLesionMediatingMediatorMolecularMusOutcomePathogenesisPathologicPeripheralPermeabilityPlayProcessPromoter RegionsProteinsRegulationReportingResearchRoleSocietiesTight JunctionsTimeTransactivationTransgenic OrganismsVascular EndotheliumZinc Fingersacute strokeagedblood-brain barrier disruptionblood-brain barrier permeabilizationbrain endothelial cellcell growthcerebral hypoperfusioncerebrovascularcerebrovascular pathologycognitive functioneffective therapygray matterhemodynamicsimmune cell infiltrateimprovedmembermigrationmouse modelneuron lossnoveloverexpressionpreservationpreventsocialtherapeutically effectivetranscription factortranscription factor KLF13vascular cognitive impairment and dementiavascular contributionswhite matterwhite matter injury
项目摘要
Vascular cognitive impairment and dementia (VCID), a type of cognitive disorder mainly induced by
cerebrovascular pathology and dysfunction, is widely recognized as the second most common cause of
dementia after Alzheimer’s disease, and results in tremendous economic and social burdens on our society.
Despite recent progress in VCID research, our understanding of cerebrovascular contributions to the
pathogenesis of VCID is still limited, and the effective therapeutic approaches for VCID are unavailable.
Krüppel-like factors (KLFs) are members of the zinc finger family of transcription factors and consist of 18
members that have been shown to play key roles in cellular growth and differentiation. Cumulative studies
have documented that several KLFs (KLF2, KLF4, KLF5, KLF6, KLF8, KLF11, KLF13, KLF14, and KLF15) are
implicated in developmental and pathological vascular processes. It is becoming apparent that KLFs are also
implicated in regulating the pathogenesis of cerebrovascular diseases and warrant further investigation. KLF11
is a unique diabetes-associated KLF transcription factor among 18 KLF family members and is highly
expressed in vascular endothelium. We reported for the first time that KLF11 functions as an important
mediator in acute stroke-induced brain injury. However, the function and mechanisms of KLF11 in regulating
cerebrovascular pathogenesis and progression of cognitive decline are totally unknown in VCID.
In our recent preliminary studies, we have shown that KLF11 expression is significantly decreased in the
mouse cerebral vasculature after VCID. Of note, EC-selective KLF11 transgenic overexpression displays
reduced cognitive impairments in the experimental VCID mouse model, whereas KLF11 genetic deficiency
results in increased cognitive impairments, white matter injury and neuronal loss. Mechanistically, we have
documented that KLF11 genetic deficiency increased BBB permeability in mice after VCID. We further found
several KLF11 binding sites in the promoter region of major endothelial tight junctions, and genetic deletion of
KLF11 in VCID mice significantly reduced cerebral expression of claudin-5. These findings have provided the
basis for our Central Hypothesis that vascular KLF11 attenuates BBB disruption and subsequent
pathological cascades after chronic cerebral hypoperfusion, thereby contributing to increased BBB
stabilization, reduced white matter/neuronal loss, and improved long-term cognitive outcomes in VCID.
Three specific aims will be performed in this proposal. Aim 1: Define the role of vascular KLF11 in long-term
cognitive disorders, brain white matter injury, and neuronal loss in experimental VCID; Aim 2: Elucidate the
mechanisms of vascular KLF11-mediated brain protection in VCID; Aim 3: Explore systematic delivery of TAT-
KLF11 protein as a potential therapy in VCID. Elucidating KLF11 cerebrovascular protection may help us to
discover vascular contribution to brain white and grey matter injury and dementia, and lead us to develop novel
and effective treatment against VCID.
血管性认知障碍与痴呆(Vascular cognitive impairment and dementia, VCID)是一种主要由
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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Kejie Yin其他文献
Kejie Yin的其他文献
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{{ truncateString('Kejie Yin', 18)}}的其他基金
Regulatory microRNAs-mediated cerebrovascular protection and traumatic braininjury
调节性 microRNA 介导的脑血管保护和创伤性脑损伤
- 批准号:
10478480 - 财政年份:2022
- 资助金额:
$ 60.95万 - 项目类别:
Role of nitro-fatty acids in BBB stabilization and post-stroke neurovascular protection
硝基脂肪酸在血脑屏障稳定和中风后神经血管保护中的作用
- 批准号:
10293575 - 财政年份:2020
- 资助金额:
$ 60.95万 - 项目类别:
Role of nitro-fatty acids in BBB stabilization and post-stroke neurovascular protection
硝基脂肪酸在血脑屏障稳定和中风后神经血管保护中的作用
- 批准号:
10007200 - 财政年份:2020
- 资助金额:
$ 60.95万 - 项目类别:
Role of nitro-fatty acids in BBB stabilization and post-stroke neurovascular protection
硝基脂肪酸在血脑屏障稳定和中风后神经血管保护中的作用
- 批准号:
10514600 - 财政年份:2020
- 资助金额:
$ 60.95万 - 项目类别:
Kruppel-like factor 11 and ischemic stroke
Kruppel 样因子 11 与缺血性中风
- 批准号:
8963735 - 财政年份:2015
- 资助金额:
$ 60.95万 - 项目类别:
Kruppel-like factor 11 and ischemic stroke
Kruppel 样因子 11 与缺血性中风
- 批准号:
9178989 - 财政年份:2015
- 资助金额:
$ 60.95万 - 项目类别:
Kruppel-like factor 11 and ischemic stroke
Kruppel 样因子 11 与缺血性中风
- 批准号:
9063097 - 财政年份:2015
- 资助金额:
$ 60.95万 - 项目类别:
Kruppel-like factor 11 and ischemic stroke
Kruppel 样因子 11 与缺血性中风
- 批准号:
9243321 - 财政年份:2015
- 资助金额:
$ 60.95万 - 项目类别:
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