权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Type I interferon-dependent mechanisms of synapse loss in lupus

狼疮突触丢失的 I 型干扰素依赖性机制

基本信息

批准号：
10433932
负责人：
Michael Craig Carroll
金额：
$ 46.17万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-16 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433932
关键词：
Affect Alzheimer&apos s Disease Anxiety Autoantibodies Autoimmune Diseases Behavior Blood Blood - brain barrier anatomy Brain Brain region Cells Central Nervous System Diseases Cerebrospinal Fluid Cognition Complement Complement component C4a Data Defect Development Disease Fc Receptor Frequencies Functional disorder Gene Expression Genes Headache High Prevalence IFNAR1 gene Immune Impaired cognition Inflammation Inflammatory Injury Interferon Receptor Interferon Type I Interferon-alpha Interferons Kidney Knowledge Lead Link Lung Lupus Mediating Mental Depression Microglia Microvascular Dysfunction Modeling Mus Neurologic Neurologic Symptoms Neurons Neuropsychiatric Systemic Lupus Erythematosus Pathogenicity Pathology Pathway interactions Patients Pattern Peripheral Phagocytes Phagocytosis Predisposition Process Production Psychoses Publishing Recombinants Schizophrenia Seizures Serum Signal Transduction Skin Social Behavior Source Symptoms Synapses Systemic Lupus Erythematosus Testing Tissues Variant age related autoreactive B cell base behavioral phenotyping blood-brain barrier permeabilization brain endothelial cell cognitive development common symptom cytokine density experience frontal lobe gray matter in vivo interferon alpha receptor lupus prone mice macrophage mouse model neurodevelopment neuron loss novel overexpression pathogenic autoantibodies prevent programs receptor relating to nervous system response social deficits spatial memory synaptic pruning uptake

项目摘要

Abstract Systemic lupus erythematosus is an incurable autoimmune disease characterized by pathogenic autoantibodies that potentiate inflammatory injury in tissues such as skin, lungs and kidneys. Lupus patients also experience neurologic symptoms that range from severe headache and seizures to neuropsychosis and are collectively referred to as CNS Lupus. We propose that neurologic symtoms result from peripheral interferon alpha that enters the brain and activates the microglia and complement -dependent pruning pathway leading to synapse loss in brain regions involved in cognition, spatial memory and social behavior. Studies in murine models of lupus suggest that peripheral immune cells and autoantibody may penetrate the blood brain barrier and induce pathology. However, in lupus patients symptoms of neuropsychosis are often detected early in disease suggesting that other factors might be involved in injury without destruction of the blood brain barrier. In our own study using a murine model of lupus, preliminary results identify an age-dependent significant increase in the frequency of activated microglia that are positive for uptake of neuronal synaptic material. Remarkably, the lupus mice develop changes in behavior that correlate with synapse loss. The pattern of microglia activation and synaptic pruning is similar to that observed during early neural development where selective synapse elimination is normal. Notably, treatment of the lupus mice in vivo with anti-interferon receptor antibody was protective. The objective of this proposal is to test our hypothesis that peripheral cytokines such as type I interferon trigger a microglia-dependent synaptic pruning program leading to increased elimination of synapses that could explain the neurological symptoms observed in lupus. The following two aims are proposed. Specific aim 1: Test the hypothesis that microglia-mediated synaptic pruning becomes activated in SLE. Based on our preliminary data, we predict that microglia-dependent synapse loss occurs in SLE mouse models and that activation of the classical complement cascade is required for this process. Specific aim 2: Test the hypothesis that increased type I interferon signaling in SLE promotes CNS dysfunction We predict that type I interferon-stimulated microglia activate a synapse pruning gene program leading to inappropriate engulfment of neuronal material and development of cognitive and social dysfunction. Moreover, preliminary results suggest that treatment with anti-IFNAR may be protective and prevent synapse loss.

摘要