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16万美国人，其中一半以上的患者将在2019年年底前死亡 这一年。出血性卒中、脑实质内出血和动脉瘤的治疗 蛛网膜下腔出血，在过去的40年里实际上一直处于停滞状态，并不是由于缺乏努力。 也许缺乏进展的原因是无法有效地解决脑部炎症 继发于外渗的红细胞(RBC)负担。在出血性卒中动物模型中，小胶质细胞 (Mg)是大脑中的组织驻留巨噬细胞，已被证明在RBC诱导的 脑部发炎。负责启动RBC诱导的脑炎症的MG受体是 Toll样受体4(TLR4)。在出血性卒中小鼠模型中，MG TLR4对这种崩溃有反应 红血球的产物可引发脑部炎症。同时抑制MG TLR4似乎可以预防 出血性卒中的脑部炎症，这一策略具有显著的免疫抑制风险。 对TLR4下游的非正则TLR4通路的调制可能会提供一些缓解 镁介导的脑炎症。 Lyn激酶(Lyn)是一种由B细胞、髓系细胞和树突状细胞表达的Src家族酪氨酸激酶。LYN是独一无二的 SFK家族在B细胞受体信号转导中既有刺激通路，也有反馈抑制通路 可以导致对配体的耐受。细菌应答中Lyn激酶调节TLR4信号的证据 PAMPS缺乏，相互矛盾，依赖于细胞类型。了解LYN对TLR4信号的调节 重症肌无力患者对红细胞刺激的反应是新颖的，可能允许调节脑部炎症 出血性中风。 我们的实验室发现MG TLR4-Lyn信号在RBC诱导的炎症和RBC中起重要作用 吞噬作用。我们的初步数据表明，这一通路的调制确实会减少神经元 细胞凋亡，在体外。我们假设，调节这一通路可以改善重症肌无力SAH后的预后 可能是其他形式的出血性中风。