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 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。