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（由申请人提供）：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）中髓磷脂的破坏和继发性神经变性。目前，人们相信MS发作是由自身反应性T细胞引发的。然后由驻留和外周骨髓细胞产生的炎症环境进一步加剧。多发性硬化症炎症发作后，炎症得到解决，但促进恢复稳态的机制仍然存在。炎症消退过程中涉及的关键事件是细胞碎片的清除和炎症程序的终止，我们的长期目标是阐明控制中枢神经系统炎症消退的机制，这将促进炎症消退。低密度脂蛋白受体相关蛋白 1 (LRP1) 是在骨髓细胞（包括中枢神经系统驻留的小胶质细胞）上高表达的清道夫受体，可促进 MS 等神经炎症性疾病的治疗新药的开发。该提议的基础是我们发现 LRP1 也可作为炎症抑制剂，因为缺乏 LRP1 的细胞在受到刺激后会表现出增强且持续的炎症反应。此外，在 MS、实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型中，骨髓细胞中 LRP1 缺失的小鼠的疾病严重程度增加。LRP1 在碎片清除和抑制中的功能。炎症将这种受体置于中心舞台，作为 MS 炎症消退的潜在调节因子，我们的假设是，骨髓细胞中的 LRP1 通过增强细胞碎片的清除和关闭炎症反应来限制 MS 期间的组织损伤。有了强有力的初步证据，这一假设将通过追求三个具体目标来解决：1）测试LRP1是否通过促进组织碎片的吞噬作用来抑制炎症2）测试骨髓LRP1对吞噬作用的贡献。 3) 使用小胶质细胞或髓样细胞中条件性缺失 LRP1 的小鼠模型系统测试 LRP1 在 EAE 过程中的功能作用。 第一个目标是，我们将研究 LRP1 介导的吞噬作用和炎症之间的相互作用。在第二个目标中，我们将使用 LRP1 介导的髓磷脂吞噬作用的双光子实时成像。研究小胶质细胞和炎症巨噬细胞 LRP1 在 EAE 病理过程中的作用我们的方法是创新的，因为我们将使用新的动物模型结合最先进的实时成像来研究清道夫受体 LRP1 在神经炎症后恢复稳态过程中的功能。我们的建议意义重大，因为这些研究将为了解 LRP1 在 MS 中的功能提供基础，最终目标是为 MS 患者开发新型抗炎治疗方法。