Wnt Signaling in Stroke

中风中的 Wnt 信号转导

• 批准号: 10019606
• 负责人: RAYMOND Charles KOEHLER
• 金额: $ 47.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019606
• 关键词: Acute; Acute Brain Injuries; Affect; Agonist; Anti-Inflammatory Agents; Antidepressive Agents; Astrocytes; Astrocytoma; Attenuated; Autologous; Blood; Blood Cells; Brain; Brain Diseases; Brain Injuries; Brain hemorrhage; Calcium; Cell physiology; Cells; Cerebral hemisphere hemorrhage; Cytoplasmic Granules; Degenerative polyarthritis; Electron Microscopy; Fluorescence-Activated Cell Sorting; Gelatinase A; Gelatinase B; Green Fluorescent Proteins; Heart failure; Hematoma; Hemoglobin; Hippocampus (Brain); Histologic; Histology; Immune; Inflammation; Inflammatory Response; Injury; Knock-out; Knockout Mice; Lead; Magnetic Resonance Imaging; Mediating; Methods; Microglia; Modeling; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Mus; Myeloid Cells; National Institute of Neurological Disorders and Stroke; Natural Immunity; Outcome; Pathologic; Pathologic Processes; Pathway interactions; Phagocytosis; Pharmacology; Phenotype; Pilot Projects; Proteins; Publishing; Recombinants; Recovery of Function; Research; Rho-associated kinase; Role; Secondary to; Signal Pathway; Signal Transduction; Signaling Protein; Slice; Stroke; TLR4 gene; Testing; Thrombin; Transgenic Mice; WNT Signaling Pathway; Whole Blood; Wild Type Mouse; Work; beta catenin; blood-brain barrier disruption; brain cell; dentate gyrus; effective therapy; frizzled related protein-3; functional outcomes; gray matter; improved; improved outcome; in vivo; inflammatory marker; inhibitor/antagonist; injury recovery; interdisciplinary approach; mRNA Expression; macrophage; neurobehavioral test; novel; planar cell polarity; post stroke; protective effect; pup; recruit; response; rho; rho GTP-Binding Proteins; therapeutic target; white matter injury

Project Summary Wnt signaling in stroke Intracerebral hemorrhage (ICH) is the most lethal but under-researched type of stroke. Therapeutic targets to minimize pathologic processes focus on mitigating inflammation and promoting hematoma clearance. Wnt signaling regulates diverse cellular activities and modulates an inflammatory response in microglia in certain brain diseases. Although much work has investigated Wnt-dependent cell genesis, a critical gap exists with respect to our understanding of how Wnt signaling regulates inflammatory responses after ICH. The secreted frizzled-related protein 3 (sFRP3, a synonym of Frzb) regulates both canonical and noncanonical Wnt pathways, and dysregulation of sFRP3 is associated with certain pathologic conditions, including osteoarthritis, astrocytoma, and heart failure. However, very few studies have investigated sFRP3 in brain, and little is currently known about the role of sFRP3/Wnt signaling in injury from stroke or ICH. The scientific objective of this R01 is to investigate whether astrocyte sFRP3 inhibits proinflammatory response, thereby reducing acute ICH injury and improving functional outcomes. By using multiple cellular, molecular, genetic, pharmacologic, histologic, and flow cytometric methods, we have obtained strong evidence to suggest a key role for sFRP3 in protection against early ICH injury: 1) sFRP3 expression level is upregulated in astrocytes in the perihematomal region early after ICH; 2) Loss/gain of sFRP3 function exacerbates/mitigates ICH injury; and 3) sFRP3 deletion increases expression of Toll-like receptor (TLR)4 and Wnt downstream molecule RhoA, as well as MMP-9 activity in the ICH brain. These novel observations support the scientific premise that astrocyte sFRP3 protects against early ICH injury and led us to hypothesize that astrocyte sFRP3 promotes microglial M2 polarization through inhibition of TLR4 signaling and that astrocyte sFRP3 attenuates brain damage through TLR4/Wnt signaling after ICH. In three specific aims, we will determine whether loss/gain of sFRP3 function exacerbates/mitigates ICH injury (Aim 1), whether astrocyte sFRP3 promotes microglial M2 polarization through inhibition of TLR4 signaling (Aim 2), and whether astrocyte sFRP3 attenuates brain injury through the TLR4/Wnt signaling pathway (Aim 3). Using multidisciplinary approaches, this study will elucidate the role of astrocyte sFRP3 after ICH and the cellular and molecular mechanisms by which astrocyte sFRP3-mediated microglial phenotypic switching mitigates gray and white matter injury, and improves functional recovery. This novel proof-of-concept work has translational potential and will stimulate more studies of sFRP3 in various brain diseases. Investigating innate immunity after stroke is a critical priority identified by the recent NINDS-SPRG.

项目总结