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（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）髓鞘破坏和继发性神经退行性变。目前，认为MS发作由自身反应性T细胞引发，然后由驻留和外周骨髓细胞产生的炎症环境进一步加剧。MS炎症发作后，炎症得到解决，但促进恢复稳态的机制仍然难以捉摸。炎症消退中涉及的关键事件是细胞碎片的去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，这将有助于开发神经炎性疾病（如MS）的新疗法。低密度脂蛋白受体相关蛋白-1（LRP 1）是在骨髓细胞（包括CNS驻留的小胶质细胞）上高度表达的清道夫受体。LRP 1促进碎片如降解的髓鞘和垂死细胞的吞噬作用，这些碎片存在于MS炎症发作期间。这一提议的基础是我们发现LRP 1也可以作为炎症抑制剂，因为缺乏LRP 1的细胞在刺激后显示出增加和持续的炎症反应。此外，在骨髓细胞中缺失LRP 1的小鼠在MS（实验性自身免疫性脑脊髓炎（EAE））的小鼠模型中具有增加的疾病严重性。LRP 1在碎片清除和炎症抑制中的功能将该受体置于中心阶段，作为MS炎症消退的潜在调节剂。我们的假设是，骨髓细胞中的LRP 1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。在强有力的初步证据的指导下，该假设将通过追求三个具体目标来解决：1）测试LRP 1是否通过促进组织碎片的吞噬来抑制炎症。2)检测髓样LRP 1对体内吞噬变性髓鞘的贡献。3)测试LRP 1在EAE期间的功能作用，使用在小胶质细胞或骨髓细胞中具有LRP 1条件性缺失的小鼠模型系统。在第一个目标下，我们将使用骨髓细胞的原代培养物研究LRP 1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LRP 1介导的髓鞘吞噬作用的双光子活体成像。在最后的目标，我们将研究小胶质细胞和炎症巨噬细胞LRP 1在EAE病理过程中的贡献。我们的方法是创新的，因为我们将研究清道夫受体LRP 1的功能，在神经炎症后恢复稳态过程中，使用新的动物模型结合最先进的CNS实时成像。我们的建议是重要的，因为这些研究将为理解LRP 1在MS中的功能提供基础，最终目标是为MS患者开发新的抗炎治疗方法。