Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury
创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制
基本信息
- 批准号:10402868
- 负责人:
- 金额:$ 37.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimalsAntisense OligonucleotidesAstrocytesBindingBloodBlood ProteinsBlood VesselsBrainCaveolaeCognitionComplexDataDepositionDiseaseEndothelial CellsEndotheliumFemaleFibrinogenHippocampus (Brain)ImmunohistochemistryImpaired cognitionImpairmentIn VitroInflammationInflammatoryIntercellular adhesion molecule 1LinkMediatingMembrane ProteinsMemoryMemory impairmentMorbidity - disease rateMusNerve DegenerationNeuronal DysfunctionPathogenicityPathologicPathologyPathway interactionsPatientsPermeabilityPhosphorylationPrPProcessProteinsReactive Oxygen SpeciesReceptor Protein-Tyrosine KinasesResearch PriorityResistanceShort-Term MemorySignal TransductionSmall Interfering RNAStainsStimulusTestingTransgenic OrganismsTraumatic Brain InjuryUnited States National Institutes of HealthVascular Cognitive ImpairmentVascular DiseasesVascular EndotheliumVascular PermeabilitiesWestern Blottingbasecaveolin 1cell motilitycerebral microvasculaturecerebrovascularcerebrovascular pathologycontrolled cortical impactdesignfluoro jadein vivoloss of functionmalemortalityneurovascularnovelobject recognitionoverexpressionprotein complextranscytosis
项目摘要
Project Summary
This application addresses problems related to vascular cognition impairment (VCI). Particularly it aims to define
mechanisms of vasculo-astrocyte functional connectivity that results in cognitive decline after inflammatory
pathologies, e.g. traumatic brain injury (TBI). It is known that increased vascular permeability is involved in
pathological alterations in neurovascular network such as accumulation of fibrinogen (Fg) and cellular prion protein
(PrPC) leading to neuronal dysfunction and degeneration. However, critical factors that initiate these effects are not
known. Our preliminary data indicated that TBI-induced an increase in blood level of Fg, called hyperfibrinogenemia
(HFg), and enhanced cerebrovascular permeability to proteins mainly via caveolar transcytosis. This effect caused
a greater deposition of Fg and increased formation of Fg and PrPC complex in vasculo-astrocyte interface, resulting
in vasculo-astrocyte physical uncoupling and astrocyte activation leading to neuronal degeneration via
overexpression of neurotrophic tyrosine receptor kinase B (TrkB) and formation of reactive oxygen species (ROS).
These effects were associated with neuronal degeneration and reduction in short-term memory (STM) in mice after
TBI. Importantly, treatment of mice with siRNA against caveolae membrane protein caveolin-1 (Cav-1) ameliorated
TBI-induced memory reduction. Based on these data, we propose a novel hypothesis that TBI-mediated
inflammation increases the blood level of Fg, which via binding to endothelial ICAM-1 activates caveolar protein
transcytosis resulting in enhanced Fg deposition and formation of Fg-PrPC complex, which cause astrocyte
activation, vasculo-astrocyte uncoupling and subsequent neuronal degeneration (via TrkB-ROS pathway) resulting
in STM reduction. This compelling hypothesis provides the crucial link between vascular dysfunction and neuronal
degeneration leading to cognition impairment during various cerebrovascular pathologies. The present study
should reveal the fundamental, previously unknown mechanism for vasculo-astrocyte uncoupling (altered
functional and physical connectivity) leading to neuronal degeneration and memory reduction after TBI. The
hypothesis will be tested with three specific aims: (1) To define whether the HFg-mediated caveolar protein
transcytosis enhances Fg deposition and Fg-PrPC complex formation in brain extravascular space during TBI. (2)
To define whether the Fg-PrPC complex formation in vasculo-astrocyte interface causes vasculo-astrocyte
uncoupling and neuronal degeneration leading to reduction in STM during TBI. (3) To define if diminishing caveolae
formation in vascular endothelium and Fg-PrPC complex formation can ameliorate neuronal degeneration and STM
reduction during TBI. Specific mechanisms of TBI-induced vasculo-astrocyte uncoupling and memory impairment,
i.e. VCI, will be studied using cultured endothelial cells and astrocytes, and C57BL/6J wild type and transgenic HFg
mice. Fg-PrPC complex and ROS formations, levels of TrkB, astrocyte activation, and neuronal degeneration
assessed by NeuN will be evaluated by immunohistochemistry and Western blot. STM will be assessed by novel
object recognition test, Barnes maze and Y-maze tests.
项目总结
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Vascular Effects on Cerebrovascular Permeability and Neurodegeneration.
- DOI:10.3390/biom13040648
- 发表时间:2023-04-04
- 期刊:
- 影响因子:5.5
- 作者:
- 通讯作者:
Fibrinogen and Neuroinflammation During Traumatic Brain Injury.
创伤性脑损伤期间的纤维蛋白原和神经炎症。
- DOI:10.1007/s12035-020-02012-2
- 发表时间:2020-11
- 期刊:
- 影响因子:5.1
- 作者:Sulimai N;Lominadze D
- 通讯作者:Lominadze D
Fibrinogen, Fibrinogen-like 1 and Fibrinogen-like 2 Proteins, and Their Effects.
- DOI:10.3390/biomedicines10071712
- 发表时间:2022-07-15
- 期刊:
- 影响因子:4.7
- 作者:
- 通讯作者:
Effects of fibrinogen synthesis inhibition on vascular cognitive impairment during traumatic brain injury in mice.
- DOI:10.1016/j.brainres.2020.147208
- 发表时间:2021-01-15
- 期刊:
- 影响因子:2.9
- 作者:Muradashvili N;Charkviani M;Sulimai N;Tyagi N;Crosby J;Lominadze D
- 通讯作者:Lominadze D
The Role of Nuclear Factor-Kappa B in Fibrinogen-Induced Inflammatory Responses in Cultured Primary Neurons.
- DOI:10.3390/biom12121741
- 发表时间:2022-11-23
- 期刊:
- 影响因子:5.5
- 作者:
- 通讯作者:
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{{ truncateString('DAVID LOMINADZE', 18)}}的其他基金
Hyperfibrinogenemia and sphingolipid-mediated cerebrovascular permeability and memory impairment during TBI
TBI期间高纤维蛋白原血症和鞘脂介导的脑血管通透性和记忆障碍
- 批准号:
10855710 - 财政年份:2023
- 资助金额:
$ 37.38万 - 项目类别:
Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury
创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制
- 批准号:
10161854 - 财政年份:2019
- 资助金额:
$ 37.38万 - 项目类别:
Mechanisms of neurodegeneration by a fibrinogen-containing protein complex during traumatic brain injury
创伤性脑损伤期间含纤维蛋白原的蛋白质复合物引起神经退行性变的机制
- 批准号:
10027325 - 财政年份:2019
- 资助金额:
$ 37.38万 - 项目类别:
Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
同型半胱氨酸诱导纤维蛋白原淀粉样蛋白斑形成的机制
- 批准号:
8599053 - 财政年份:2013
- 资助金额:
$ 37.38万 - 项目类别:
Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
同型半胱氨酸诱导纤维蛋白原淀粉样蛋白斑形成的机制
- 批准号:
8689198 - 财政年份:2013
- 资助金额:
$ 37.38万 - 项目类别:
Fibronogen-Induced Vasconstriction during Hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7838826 - 财政年份:2009
- 资助金额:
$ 37.38万 - 项目类别:
Fibrinogen-induced vasoconstriction during hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7209670 - 财政年份:2007
- 资助金额:
$ 37.38万 - 项目类别:
Fibrinogen-Induced Vasoconstriction during Hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7788167 - 财政年份:2007
- 资助金额:
$ 37.38万 - 项目类别:
Fibrinogen-induced vasoconstriction during hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7360319 - 财政年份:2007
- 资助金额:
$ 37.38万 - 项目类别:
Fibrinogen-Induced Vasoconstriction during Hypertension
高血压期间纤维蛋白原诱导的血管收缩
- 批准号:
7575795 - 财政年份:2007
- 资助金额:
$ 37.38万 - 项目类别:
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