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年底前死亡