Modulation of the TLR4-Lyn interaction in SAH

SAH 中 TLR4-Lyn 相互作用的调节

• 批准号: 10348220
• 负责人: Khalid A. Hanafy
• 金额: $ 44.39万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10348220
• 关键词: Address; Adult; Affect; American; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Antigen-Presenting Cells; B-Cell Antigen Receptor; B-Lymphocytes; Brain; Brain hemorrhage; Cerebrum; Clinical Trials; Co-Immunoprecipitations; Data; Dendritic Cells; Dyes; Erythrocytes; Family; Feedback; Flow Cytometry; Gender; Hematoma; Heme; Hemorrhage; Hour; Immunosuppression; In Vitro; Infectious Agent; Inflammation; Inflammatory; Injections; Lead; Ligands; Lysosomes; Measures; Mediating; Microglia; Modeling; Molecular; Mus; Myeloid Cells; NF-kappa B; Names; Neurological outcome; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Phagocytosis; Phagolysosome; Phagosomes; Phosphorylation; Phosphotransferases; Play; Receptor Signaling; Regulation; Resolution; Risk; Role; Secondary to; Septic Shock; Signal Transduction; Signal Transduction Pathway; Stimulus; Subarachnoid Hemorrhage; TLR4 gene; Testing; Tissues; brain magnetic resonance imaging; cell type; cognitive function; dentate gyrus; experimental study; improved; improved outcome; in vivo; inflammatory marker; inhibitor; macrophage; mouse model; neuroinflammation; neuron apoptosis; novel; pathogen; pathogenic bacteria; prevent; receptor; response; src-Family Kinases; virtual

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结束时死亡 一年。两种形式的出血性中风，脑内大义和动脉瘤的治疗 在过去的40年中，蛛网膜下腔出血一直处于虚拟的停滞状态，而不是由于缺乏努力而导致的。 也许缺乏进步的原因是无法有效解决大脑炎症 继发于奢侈的红细胞（RBC）负担。在出血性中风的动物模型中，小胶质细胞 （mg）是大脑的组织驻留巨噬细胞，已显示出在RBC诱导的 大脑炎症。负责引发RBC引起的大脑炎症的MG受体是 像受体4（TLR4）一样收费。在出血性中风的鼠标模型中，Mg TLR4对故障做出了反应 RBC的产物发起脑炎。抑制Mg TLR4似乎是可行的 出血性中风中的大脑炎症，该策略具有免疫抑制的重大风险。 TLR4下游的非规范TLR4途径的调节可能会提供一些喘息的机会 MG介导的大脑炎症。 Lyn激酶（Lyn）是由B，髓样和树突状细胞表达的SRC家庭酪氨酸激酶。林恩在 SFK家族在B细胞受体信号中具有刺激性和反馈抑制途径 可以导致配体耐受性。 TLR4信号传导的Lyn激酶调节的证据响应细菌 弹药很少，矛盾和细胞类型依赖。了解LYN的TLR4信号传导的调节 对MG中RBC刺激的反应是新颖的，可以调节大脑炎症 出血中风。 我们的实验室发现MG TLR4-LYN信号对于RBC诱导的炎症和RBC很重要 吞噬作用。我们的初步数据表明，该途径的调节确实确实降低了神经元 凋亡，体外。我们假设在MG中对该途径的调节可以改善SAH之后的结果 可能是其他形式的出血性中风。