The role of TWEAK and Fn14 in the Pathogenesis and Treatment of Neuropsychiatric

TWEAK 和 Fn14 在神经精神疾病发病机制和治疗中的作用

• 批准号: 8911775
• 负责人: CHAIM PUTTERMAN
• 金额: $ 40.44万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911775
• 关键词: Antibodies; Apoptosis; Apoptosis Promoter; Astrocytes; Autoantibodies; Autoimmune Process; Behavioral Model; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain imaging; Cell Survival; Cells; Cognitive; Defect; Disease; Endothelial Cells; Etiology; Evans blue stain; Family member; Functional disorder; High Prevalence; Human; Impaired cognition; In Vitro; Inbred MRL lpr Mice; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Knock-out; Knockout Mice; Ligands; Lupus; Measures; Mediator of activation protein; Mental Depression; Microglia; Modeling; Mood Disorders; Mouse Strains; Mus; Nephritis; Nerve Degeneration; Neuraxis; Neurologic; Neurons; Neuropsychiatric Systemic Lupus Erythematosus; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Permeability; Play; Relative (related person); Role; Severities; Signal Transduction; Signs and Symptoms; Symptoms; Systemic Lupus Erythematosus; TNF gene; Therapeutic; Therapeutic Studies; Tight Junctions; Time; Transplantation; behavioral outcome; behavioral study; brain cell; cell type; cytokine; early onset; in vivo; juvenile animal; lupus prone mice; member; neurobehavioral; neuropsychiatry; neurotransmitter metabolism; novel strategies; outcome forecast; protein expression; public health relevance; receptor; systemic autoimmune disease; therapeutic target

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a high incidence of neuropsychiatric involvement. Signs and symptoms of neuropsychiatric SLE (NPSLE) are among the earliest and most common manifestations in lupus patients, and can occur independently of non-neurologic disease. In the MRL/lpr strain as well, a commonly used murine lupus model, behavioral changes consistent with severe depression and impaired cognition are evident in young animals before increased autoantibody titers and other major organ involvement. These and other studies indicate that NPSLE is indeed a primary disease manifestation. Nevertheless, despite the high prevalence of NPSLE and its poor prognosis, the pathogenesis is not well understood and optimal treatment is still unclear. Previous studies have largely focused on potential etiological factors such as autoantibodies and neurodegeneration that often become apparent only relatively late after onset of SLE. These factors do not adequately explain the early onset of NPSLE observed in lupus mice or in many patients. Among putative regulators of early CNS dysfunction, cytokines can both directly and indirectly promote negative CNS outcomes via a range of different mechanisms. These include effects on autoantibodies, increasing secretion of cytokines and other inflammatory mediators, loss of integrity of the blood brain barrier (BBB), and alteration of neurotransmitter metabolism. Members of the TNF superfamily are important in the pathogenesis of SLE. TWEAK is a secreted member of this cytokine superfamily, with pleotropic effects on multiple cell types, including promotion of inflammation and context-dependent effects on cell survival and apoptosis. The TWEAK receptor, Fn14, is expressed in astrocytes, microglia, brain microvascular endothelial cells, and neurons. Furthermore, TWEAK induces the release of other inflammatory cytokines known to play a role in NPSLE. Recently, we found that Fn14 deficient MRL/lpr lupus mice display significantly less depression and cognitive abnormalities than Fn14 sufficient MRL/lpr littermates, while human NPSLE is associated with high TWEAK levels in the CSF. Our preliminary studies strongly support the hypotheses that 1) TWEAK plays a major role in the etiology of NPSLE; 2) TWEAK blockade may be a novel approach for the treatment of neuropsychiatric disease. In this proposal, we will confirm the role of TWEAK in the pathogenesis of NPSLE, examine the mechanisms by which TWEAK signaling induces neurobehavioral abnormalities in lupus, and study the therapeutic potential of TWEAK inhibition for treating manifestations of NPSLE.

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种系统性自身免疫性疾病，神经精神受累的发生率很高。神经精神系统性红斑狼疮 (NPSLE) 的体征和症状是狼疮患者最早和最常见的表现之一，并且可以独立于非神经系统疾病而发生。在 MRL/lpr 品系（一种常用的小鼠狼疮模型）中，在自身抗体滴度增加和其他主要器官受累之前，幼年动物中与严重抑郁和认知受损一致的行为变化也很明显。这些和其他研究表明 NPSLE 确实是一种原发性疾病表现。然而，尽管 NPSLE 患病率高且预后差，但其发病机制尚不清楚，最佳治疗方案仍不清楚。先前的研究主要集中在潜在的病因上，例如自身抗体和神经变性，这些因素通常在系统性红斑狼疮发病后相对较晚的时候才变得明显。这些因素并不能充分解释在狼疮小鼠或许多患者中观察到的 NPSLE 早期发作。在早期中枢神经系统功能障碍的假定调节因子中，细胞因子可以通过一系列不同的机制直接或间接促进中枢神经系统的负面结果。这些包括对自身抗体的影响、细胞因子和其他炎症介质分泌的增加、血脑屏障 (BBB) 完整性的丧失以及 神经递质代谢。 TNF 超家族成员在 SLE 的发病机制中发挥着重要作用。 TWEAK 是该细胞因子超家族的分泌成员，对多种细胞类型具有多效性，包括促进炎症以及对细胞存活和凋亡的环境依赖性影响。 TWEAK 受体 Fn14 在星形胶质细胞、小胶质细胞、脑微血管内皮细胞和神经元中表达。此外，TWEAK 还能诱导已知在 NPSLE 中发挥作用的其他炎症细胞因子的释放。最近，我们发现 Fn14 缺陷的 MRL/lpr 狼疮小鼠比 Fn14 充足的 MRL/lpr 同窝小鼠表现出明显更少的抑郁和认知异常，而人类 NPSLE 与 CSF 中的高 TWEAK 水平相关。我们的初步研究有力地支持了以下假设：1）TWEAK 在 NPSLE 的病因学中发挥着重要作用； 2）TWEAK阻断可能是治疗神经精神疾病的新方法。在本提案中，我们将确认 TWEAK 在 NPSLE 发病机制中的作用，检查 TWEAK 信号传导诱导狼疮神经行为异常的机制，并研究 TWEAK 抑制治疗 NPSLE 表现的治疗潜力。