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The regulation and function of TRPM7 in inflammation

TRPM7在炎症中的调控及功能

基本信息

批准号：
9198955
负责人：
BIMAL N. DESAI
金额：
$ 35.55万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198955
关键词：
Adaptive Immune System Adverse effects Alzheimer&apos s Disease American Atherosclerosis Autoimmune Diseases Biological CD95 Antigens Caspase Cations Cell Nucleus Cell membrane Cells Cessation of life Cleaved cell Clinical Complex Disease Drug Targeting Economics Employee Strikes Endocytosis Gene Expression Genes Human Immune Immune system In Vitro Inflammation Inflammatory Length Ligands Link Macrophage Activation Measures Mediating Modeling Molecular Molecular Target Mus Myelogenous Natural Immunity Non-Insulin-Dependent Diabetes Mellitus Nuclear Export Outcome Pathology Pathway interactions Pharmaceutical Preparations Phosphotransferases Play Positioning Attribute Probability Protein-Serine-Threonine Kinases Reagent Receptor Signaling Recruitment Activity Regulation Regulation of Proteolysis Resistance Role Signal Transduction Site Stem cells Stimulus T-Lymphocyte TLR4 gene TRP channel Testing Tissues Transcription Repressor/Corepressor Transcriptional Regulation Tumor Necrosis Factor Receptor United States National Institutes of Health Variant age related in vivo innovation insight interdisciplinary approach macrophage mutant novel public health relevance receptor response small molecule

项目摘要

DESCRIPTION (provided by applicant): According to the NIH, 20.5 million Americans suffer from autoimmune diseases. Additionally, inflammation contributes potently to the progression and pathology of some age-related diseases, such as Alzheimer's disease, atherosclerosis and type 2 diabetes. Severe inflammatory diseases are treated by blocking the pro-inflammatory pathways, such as TNF receptor signaling, using biological drugs. But the clinical outcome is often uncertain and plagued by significant adverse effects. Characterization of novel regulators of these inflammatory pathways that are "druggable", by more affordable small molecules is therefore of clinical and economic significance. The function of TRP channels, an exciting class of drug targets, in inflammation remains undefined. TRPM7, a TRP channel that contains a cation-conducting pore and a kinase domain, is highly expressed in the immune cells. By generating mouse lines with global and tissue-specific deletion of Trpm7, we discovered a crucial role for TRPM7 in the immune system, and now, we have uncovered a striking role for TRPM7 in macrophage activation, an essential checkpoint in inflammation. Our central hypothesis is that: Caspase-mediated proteolytic regulation of TRPM7 is essential for inflammatory signaling in macrophages. Our specific aims are: (1) Define the regulation of TRPM7 by inflammatory caspases in macrophages; (2) Define the function of TRPM7 during Fas and TLR4 signaling in macrophages. Defining how caspase-mediated cleavage of TRPM7 controls Fas and TLR4 signaling during macrophage activation will advance TRPM7 as a molecular target in inflammatory diseases. Integration of multidisciplinary approaches, novel mouse lines and innovative molecular reagents uniquely position us to fill this gap of broad significance to inflammatory diseases in humans.