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美国人，这些患者中有一半以上将在年底前死亡。 当年两种形式的出血性卒中（脑实质内出血和脑出血）的治疗 蛛网膜下腔出血，在过去的40年里一直处于实质上的停滞状态，而不是因为缺乏努力。 也许缺乏进展的原因是无法有效地解决大脑炎症 继发于外渗的红细胞（RBC）负荷。在出血性中风的动物模型中， (MG)脑组织中的巨噬细胞，已被证明在RBC诱导的 脑炎症负责启动RBC诱导的脑炎症的MG受体是 Toll样受体4（TLR 4）。在出血性中风的小鼠模型中，MG TLR 4响应于 红细胞的产物引发大脑炎症。虽然抑制MG TLR 4似乎是可行的， 在出血性中风的脑炎症中，这种策略具有显著的免疫抑制风险。 调节TLR 4下游的非经典TLR 4途径可能会缓解TLR 4的作用。 MG介导的脑炎症。 林恩激酶（林恩）是由B、髓样和树突细胞表达的Src家族酪氨酸激酶。林恩是独一无二的， SFK家族，因为它在B细胞受体信号传导中具有刺激和反馈抑制途径， 可导致配体耐受性。林恩激酶调节TLR 4信号转导应答细菌感染的证据 PAMPs是缺乏的、矛盾的和依赖于细胞类型的。了解林恩对TLR 4信号传导的调节， MG患者对RBC刺激的反应是新颖的，并且可以允许MG患者脑炎症的调节。 出血性中风 我们的实验室已经发现MG TLR 4-林恩信号传导对于RBC诱导的炎症和RBC诱导的炎症是重要的。 吞噬作用我们的初步数据表明，调节这一途径确实会减少神经元的 细胞凋亡，体外。我们假设MG中该通路的调节可以改善SAH后的结果， 可能是其他形式的出血性中风。