A Macrophage Cation Channel in Prevention and Recovery from Inflammatory Injury

巨噬细胞阳离子通道在炎症损伤预防和恢复中的作用

• 批准号: 9519646
• 负责人: MICHAEL D CARRITHERS
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519646
• 关键词: ATF2 gene; Address; Adoptive Cell Transfers; Adoptive Transfer; Alternative Splicing; Animal Model; Anti-inflammatory; Autoimmune Diseases; Autoimmune Process; Biochemical; Bone Marrow; Brain; Calcium; Calcium Oscillations; Cardiac; Caring; Cations; Cell Therapy; Cells; Chronic; Chronic Disease; Clinical; Couples; Cyclic AMP; Cytology; Data; Disease; Endosomes; Experimental Autoimmune Encephalomyelitis; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Home environment; Human; Image; Immune; Immunophenotyping; In Vitro; Inflammation; Inflammatory; Injury; Knock-in; Laboratories; Lesion; Lymphocyte Function; Mediating; Modeling; Molecular; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Neurologic; Nodule; Pathway interactions; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Phenotype; Prevention; Property; Proteins; Proteomics; RNA Splicing; Recovery; Regulation; Research; Resolution; Role; Services; Signal Pathway; Signal Transduction; Site; Sodium Channel; Spinal Cord; Spinal Cord Lesions; Symptoms; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Variant; Veterans; Wild Type Mouse; Work; base; care costs; cell type; central nervous system injury; cost; disability; experimental study; in vivo; innovation; intercellular communication; macrophage; mouse model; multiple sclerosis patient; multiple sclerosis treatment; novel; novel strategies; organelle movement; polarized cell; potassium ion; prevent; protein expression; public health relevance; release of sequestered calcium ion into cytoplasm; repaired; selective expression; sodium ion; targeted treatment; transcription factor; voltage; young adult

DESCRIPTION (provided by applicant): Existing therapies for autoimmune and inflammatory diseases have minimal effects on resolution and recovery from chronic injury. There is also a fundamental gap in understanding how macrophages regulate cellular phenotype to mediate either injury or repair. The long-term goal is to develop treatments that prevent and reverse chronic inflammatory injury. Using a combination of cellular, genomic, proteomic and in vivo approaches, a novel splice variant of the human sodium channel gene, SCN5A, has been identified as a central regulator of anti-inflammatory macrophage signaling. This splice variant encodes a novel, endosomal cation channel that couples intracellular calcium flux to downstream signaling and gene transcription. Because this splice variant is not expressed in mice, a transgenic knock-in model, the C57BL6cfms-hSCN5A mouse, was developed to study its in vivo function in macrophages. Transfer of bone marrow derived macrophages from these mice mediates clinical recovery in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). The objective of this study is to characterize the SCN5A signaling network in macrophages and determine how it regulates clinical recovery in the EAE model of chronic inflammatory disease. The central hypothesis is that persistent expression of SCN5A in macrophages initiates and maintains a cellular phenotype that enhances recovery from inflammatory injury. The rationale for this study is that understanding this mechanism will lead to innovative approaches to prevent and treat chronic inflammatory disease. The hypothesis will be tested in two specific aims: 1. Determine how the SCN5A variant cation channel regulates macrophage phenotype. 2. Analyze how SCN5A+ macrophages mediate recovery during EAE. Based on preliminary data, the working model is that endosomal channel activity mediates short-term biochemical signaling and long-term gene expression patterns that determine and maintain cellular phenotype. In Aim 1, channel-dependent regulation of cytosolic calcium, cyclic AMP, and activating transcription factor 2 (ATF2) pathways will be examined. The experimental approaches will include a combination of existing biochemical, imaging and molecular techniques in mouse and human primary macrophages. In Aim 2, the EAE model will be utilized to assess this pathway in vivo and determine how SCN5A+ macrophages mediate recovery from inflammatory injury. In vivo gene and protein expression will be analyzed and correlated with in vitro assessment of SCN5A regulation of macrophage vesicular secretion and intercellular communication. The proposed work is innovative because it represents a new approach to regulate macrophage function and treat chronic inflammatory disease. It is significant because promotion of recovery in MS and other chronic inflammatory diseases represents an unmet therapeutic need.

描述（由申请人提供）：