Role of LRP1 in NF-kB mediated neuroinflammation

LRP1 在 NF-kB 介导的神经炎症中的作用

基本信息

批准号：
9411768
负责人：
Alban P Gaultier
金额：
$ 36.7万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/9411768
关键词：
Address Animal Model 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 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 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

项目摘要

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.