Role of LRP1 in NF-kB mediated neuroinflammation

LRP1 在 NF-kB 介导的神经炎症中的作用

• 批准号: 9197702
• 负责人: Alban P Gaultier
• 金额: $ 39.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197702
• 关键词: Address; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Apoptotic; Autoimmune Diseases; Binding; Biological Models; Brain; Cells; Clinical; Data; Demyelinations; Development; Disease; Disease Progression; Disease remission; Endocytosis; Event; Excision; Exhibits; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Foundations; Goals; Homeostasis; Image; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injectable; Knock-out; LDL-Receptor Related Protein 1; Label; Light; Lipoprotein Receptor; Mediating; Microglia; Microscopy; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Myelogenous; Myeloid Cells; NF-kappa B; Necrosis; Nerve; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Pathology; Patients; Peripheral; Phagocytes; Phagocytosis; Pharmacology; Play; Production; Proteins; Regulation; Resolution; Role; SJL Mouse; Severity of illness; Signal Pathway; Signal Transduction; Symptoms; T-Lymphocyte; Testing; Tissues; autoreactive T cell; cell type; cytokine; experimental study; genetic manipulation; healing; in vivo; inflammatory milieu; inhibitor/antagonist; innovation; macrophage; mouse model; multiple sclerosis patient; multiple sclerosis treatment; neuroinflammation; novel; novel therapeutics; programs; public health relevance; receptor; scavenger receptor; therapeutic development; two-photon

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune disease characterized by the destruction of myelin in the central nervous system (CNS) and secondary neurodegeneration. Currently, it is believed that an MS episode is initiated by autoreactive T-cells and then further exacerbated by an inflammatory milieu created by the resident and peripheral myeloid cells. After an MS inflammatory episode, inflammation is resolved, but the mechanisms that promote the return to homeostasis remain elusive. Key events involved in the resolution of inflammation are the removal of cellular debris and the termination of the inflammatory program. Our long-term goal is to shed light on the mechanisms that control the resolution of inflammation in the CNS, which will facilitate the development of novel therapeutics for neuroinflammatory disorders such as MS. Low density lipoprotein receptor-related protein-1 (LRP1) is scavenger receptor that is highly expressed on myeloid cells, including the CNS-resident microglia. LRP1 promotes the phagocytosis of debris such as degraded myelin and dying cells, which are present during MS inflammatory episodes. The foundation of this proposal is our discovery that LRP1 also functions as an inhibitor of inflammation, as cells lacking LRP1 display increased and sustained inflammatory responses following stimulation. Furthermore, mice with the deletion of LRP1 in myeloid cells have increased disease severity in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Functions of LRP1 in debris clearance and inhibition of inflammation put this receptor at the center stage as a potential regulator of the resolution of inflammation in MS. Our hypothesis is that LRP1 in myeloid cells limits tissue damage during MS by enhancing the removal of cellular debris and by shutting down the inflammatory response. Guided by strong preliminary evidence, this hypothesis will be addressed by pursuing three specific aims: 1) Test if LRP1 inhibits inflammation by promoting phagocytosis of tissue debris. 2) Test the contribution of myeloid LRP1 to the phagocytosis of degenerated myelin in vivo. 3) Test the functional role of LRP1 during EAE, using mouse model systems with the conditional deletion of LRP1 in microglia or myeloid cells. Under the first aim, we will study the cross-talk between LRP1 mediated phagocytosis and inflammation using primary cultures of myeloid cells. In the second aim, we will use two-photon live imaging of LRP1 mediated myelin phagocytosis. In the final aim, we will study the contribution of microglial and inflammatory macrophage LRP1 during EAE pathology. Our approach is innovative because we will investigate the function of a scavenger receptor, LRP1, during the return to homeostasis after neuroinflammation using new animal models combined with the state of the art live imaging in the CNS. Our proposal is significant because these studies will provide the basis for understanding the function of LRP1 in MS with the ultimate goal of developing novel anti-inflammatory treatments for MS patients.

 描述（由适用提供）：多发性硬化症（MS）是一种自身免疫性疾病，其特征是中枢神经系统（CNS）和次生神经变性中的髓磷脂破坏。目前，据认为，自动反应性T细胞引发了MS发作，然后被居民和外围髓样细胞产生的炎症环境进一步加剧。经过MS炎症发作后，解决了炎症，但是促进回归体内平衡的机制仍然难以捉摸。炎症分辨率涉及的关键事件是清除细胞碎片和炎症计划的终止。我们的长期目标是阐明控制中枢神经系统中炎症的机制，这将有助于开发用于神经炎症性疾病（如MS）的新型治疗。低密度脂蛋白受体相关蛋白-1（LRP1）是清道夫受体，在包括CNS居民小胶质细胞在内的髓样细胞上高度表达。 LRP1促进碎屑的吞噬作用，例如降解的髓磷脂和垂死细胞，这些细胞在MS炎症发作期间存在。该提案的基础是我们发现LRP1还起着炎症的抑制剂的作用，因为缺乏LRP1的细胞显示出刺激后增加和持续的炎症反应。此外，在MS的小鼠模型，实验性自身免疫性脑脊髓炎（EAE）中，髓样细胞中LRP1缺失的小鼠的疾病严重程度增加。 LRP1在碎片清除和感染抑制中的功能使该受体处于中心阶段，作为MS中感染分辨率的潜在调节剂。我们的假设是，通过增强细胞碎屑的去除并通过关闭炎症反应，LRP1在MS期间限制了组织损伤。在有力的初步证据的指导下，将通过追求三个特定目的来解决该假设：1）测试LRP1是否通过促进组织碎片的吞噬作用抑制感染。 2）测试髓样LRP1对体内髓磷脂的吞噬作用的贡献。 3）测试LRP1在EAE期间的功能作用，使用小鼠模型系统在小胶质细胞或髓样细胞中具有条件缺失的小鼠模型系统。在第一个目标下，我们将研究LRP1介导的吞噬作用与使用髓样细胞的原代培养物之间的串扰。在第二个目标中，我们将使用LRP1介导的髓磷脂吞噬作用的两光子实时成像。在最终目标中，我们将研究EAE病理学期间小胶质细胞和炎症性巨噬细胞LRP1的贡献。我们的方法具有创新性，因为我们将在神经炎症后使用新动物模型与中枢神经系统中最先进的现场成像结合使用神经炎症后返回稳态后的稳态性骨骼内骨骼。我们的建议很重要，因为这些研究将为理解MS中LRP1功能的功能提供基础，其最终目的是为MS患者开发新型的抗炎治疗。