Modulation of the TLR4-Lyn interaction in SAH
SAH 中 TLR4-Lyn 相互作用的调节
基本信息
- 批准号:10348220
- 负责人:
- 金额:$ 44.39万
- 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:2021-12-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAmericanAneurysmal Subarachnoid HemorrhagesAnimal ModelAntigen-Presenting CellsB-Cell Antigen ReceptorB-LymphocytesBrainBrain hemorrhageCerebrumClinical TrialsCo-ImmunoprecipitationsDataDendritic CellsDyesErythrocytesFamilyFeedbackFlow CytometryGenderHematomaHemeHemorrhageHourImmunosuppressionIn VitroInfectious AgentInflammationInflammatoryInjectionsLeadLigandsLysosomesMeasuresMediatingMicrogliaModelingMolecularMusMyeloid CellsNF-kappa BNamesNeurological outcomeOperative Surgical ProceduresOutcomePathway interactionsPatientsPatternPhagocytosisPhagolysosomePhagosomesPhosphorylationPhosphotransferasesPlayReceptor SignalingRegulationResolutionRiskRoleSecondary toSeptic ShockSignal TransductionSignal Transduction PathwayStimulusSubarachnoid HemorrhageTLR4 geneTestingTissuesbrain magnetic resonance imagingcell typecognitive functiondentate gyrusexperimental studyimprovedimproved outcomein vivoinflammatory markerinhibitormacrophagemouse modelneuroinflammationneuron apoptosisnovelpathogenpathogenic bacteriapreventreceptorresponsesrc-Family Kinasesvirtual
项目摘要
Hemorrhagic stroke affects 160,000 Americans per year and over half of these patients will die by the end of
the year. Treatment for both forms of hemorrhagic stroke, intraparenchymal hemorrhage and aneurysmal
subarachnoid hemorrhage, have been at a virtual standstill for the last 40 years, and not due to lack of effort.
Perhaps the reason for the lack of progress is an inability to effectively address the cerebral inflammation
secondary to the extravasated red blood cell (RBC) burden. In animal models of hemorrhagic stroke, microglia
(MG), the tissue resident macrophages of the brain, have been shown to play a critical role in RBC-induced
cerebral inflammation. The MG receptor that is responsible for initiating RBC-induced cerebral inflammation is
Toll Like Receptor 4 (TLR4). In mouse models of hemorrhagic stroke, MG TLR4 responds to the breakdown
products of RBCs to initiate cerebral inflammation. While inhibiting MG TLR4 would seem feasible to prevent
cerebral inflammation in hemorrhagic stroke, this strategy carries a significant risk of immunosuppression.
Modulation of non-canonical TLR4 pathways that are downstream of TLR4 may offer some respite against
MG-mediated cerebral inflammation.
Lyn kinase (Lyn) is a Src-family tyrosine kinase expressed by B, myeloid, and dendritic cells. Lyn is unique in
the SFK family in that it has both stimulatory and feedback-inhibitory pathways in B cell receptor signaling that
can lead to ligand tolerance. Evidence for Lyn kinase regulation of TLR4 signaling in response to bacterial
PAMPs is scant, contradictory, and cell type dependent. Understanding Lyn regulation of TLR4 signaling in
response to an RBC stimulus in MG is novel, and could allow for the modulation of cerebral inflammation in
hemorrhagic stroke.
Our lab has found that MG TLR4-Lyn signaling is important for RBC-induced inflammation and RBC
phagocytosis. Our preliminary data indicates that modulation of this pathway does indeed decrease neuronal
apoptosis, in vitro. We hypothesize that modulation of this pathway in MG can improve outcome after SAH and
possibly other forms of hemorrhagic stroke.
出血性中风每年影响 160,000 名美国人,其中一半以上的患者将在 2020 年底死亡
那一年。治疗两种形式的出血性中风、实质内出血和动脉瘤性中风
蛛网膜下腔出血的治疗在过去 40 年里几乎处于停滞状态,并不是因为缺乏努力。
也许缺乏进展的原因是无法有效解决脑部炎症
继发于红细胞外渗(RBC)负担。在出血性中风的动物模型中,小胶质细胞
(MG) 是大脑中的组织驻留巨噬细胞,已被证明在红细胞诱导的
脑部炎症。负责引发红细胞诱导的脑炎症的 MG 受体是
Toll 样受体 4 (TLR4)。在出血性中风的小鼠模型中,MG TLR4 对崩溃做出反应
红细胞的产物引发脑炎症。虽然抑制 MG TLR4 似乎可以预防
出血性中风中的脑炎症,这种策略具有显着的免疫抑制风险。
TLR4 下游的非经典 TLR4 通路的调节可能会提供一些喘息的机会
MG 介导的脑炎症。
Lyn 激酶 (Lyn) 是由 B、骨髓和树突细胞表达的 Src 家族酪氨酸激酶。林的独特之处在于
SFK 家族的特点是它在 B 细胞受体信号传导中同时具有刺激和反馈抑制途径
可导致配体耐受。 Lyn 激酶调节 TLR4 信号响应细菌的证据
PAMP 缺乏、矛盾且依赖于细胞类型。了解 Lyn 对 TLR4 信号传导的调节
MG 对红细胞刺激的反应是新颖的,并且可以调节 MG 中的脑炎症
出血性中风。
我们的实验室发现 MG TLR4-Lyn 信号传导对于 RBC 诱导的炎症和 RBC 很重要
吞噬作用。我们的初步数据表明,调节该途径确实会减少神经元
细胞凋亡,体外。我们假设调节 MG 中的这条通路可以改善 SAH 后的预后
可能是其他形式的出血性中风。
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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Khalid A. Hanafy其他文献
TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential
- DOI:
10.1007/s12035-024-04518-5 - 发表时间:
2024-09-28 - 期刊:
- 影响因子:4.300
- 作者:
Feng Zhang;Hritik Mehta;Hadi Hasan Choudhary;Rezwanul Islam;Khalid A. Hanafy - 通讯作者:
Khalid A. Hanafy
We can Still Learn from a Negative Study
- DOI:
10.1007/s12028-023-01807-0 - 发表时间:
2023-08-03 - 期刊:
- 影响因子:3.600
- 作者:
Khalid A. Hanafy - 通讯作者:
Khalid A. Hanafy
Robotically assisted transcranial Doppler with artificial intelligence for assessment of cerebral vasospasm after subarachnoid hemorrhage
机器人辅助人工智能经颅多普勒评估蛛网膜下腔出血后脑血管痉挛
- DOI:
10.18700/jnc.200002 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Shooka Esmaeeli;Courtney M. Hrdlicka;Andres Brenes Bastos;Jeffrey Wang;S. Gomez;Khalid A. Hanafy;V. Lioutas;C. Ogilvy;A. Thomas;S. Shaefi;C. Fehnel;A. Nozari - 通讯作者:
A. Nozari
The doctor-patient perception mismatch: Improving approaches to assessing outcomes after ischemic stroke treated with reperfusion therapy
- DOI:
10.1016/j.jocn.2024.110981 - 发表时间:
2025-02-01 - 期刊:
- 影响因子:
- 作者:
Jane Khalife;Mary Penckofer;Michael J. Dubinski;Danielle C. Brown;Kenyon Sprankle;Taryn Hester;Marta Olive Gadea;Federica Rizzo;Marc Ribo;H.Christian Schumacher;Jesse M. Thon;Tudor G. Jovin;Manisha Koneru;Khalid A. Hanafy - 通讯作者:
Khalid A. Hanafy
Cell Death and Recovery in Traumatic Brain Injury
- DOI:
10.1007/s13311-020-00840-7 - 发表时间:
2020-04-01 - 期刊:
- 影响因子:
- 作者:
Yosuke Akamatsu;Khalid A. Hanafy - 通讯作者:
Khalid A. Hanafy
Khalid A. Hanafy的其他文献
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{{ truncateString('Khalid A. Hanafy', 18)}}的其他基金
Modulation of the TLR4-Lyn interaction in SAH
SAH 中 TLR4-Lyn 相互作用的调节
- 批准号:
10844778 - 财政年份:2023
- 资助金额:
$ 44.39万 - 项目类别:
Modulation of the TLR4-Lyn interaction in SAH
SAH 中 TLR4-Lyn 相互作用的调节
- 批准号:
10529343 - 财政年份:2021
- 资助金额:
$ 44.39万 - 项目类别:
Human Cerebrospinal Fluid Macrophages and Outcome in Subarachnoid Hemorrhage
人脑脊液巨噬细胞和蛛网膜下腔出血的结果
- 批准号:
10372925 - 财政年份:2021
- 资助金额:
$ 44.39万 - 项目类别:
Modulation of the TLR4-Lyn interaction in SAH
SAH 中 TLR4-Lyn 相互作用的调节
- 批准号:
10274359 - 财政年份:2020
- 资助金额:
$ 44.39万 - 项目类别:
The role of TLR4-dependent sterile inflammation in mediating adverse outcomes after SAH
TLR4依赖性无菌炎症在介导SAH后不良后果中的作用
- 批准号:
9504669 - 财政年份:2017
- 资助金额:
$ 44.39万 - 项目类别:
The role of TLR4-dependent sterile inflammation in mediating adverse outcomes after SAH
TLR4依赖性无菌炎症在介导SAH后不良后果中的作用
- 批准号:
9386587 - 财政年份:2017
- 资助金额:
$ 44.39万 - 项目类别:
Microglial Signal Transduction in Fever and Vasospasm after Subarachnoid Hemorrha
蛛网膜下腔出血后发热和血管痉挛中的小胶质细胞信号转导
- 批准号:
8868189 - 财政年份:2012
- 资助金额:
$ 44.39万 - 项目类别:
Microglial Signal Transduction in Fever and Vasospasm after Subarachnoid Hemorrha
蛛网膜下腔出血后发热和血管痉挛中的小胶质细胞信号转导
- 批准号:
8437024 - 财政年份:2012
- 资助金额:
$ 44.39万 - 项目类别:
Microglial Signal Transduction in Fever and Vasospasm after Subarachnoid Hemorrha
蛛网膜下腔出血后发热和血管痉挛中的小胶质细胞信号转导
- 批准号:
8551758 - 财政年份:2012
- 资助金额:
$ 44.39万 - 项目类别:
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