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Regulation of Innate Immune Signaling by Lyn Kinase

Lyn 激酶对先天免疫信号的调节

基本信息

批准号：
9208733
负责人：
Clifford A Lowell
金额：
$ 39.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9208733
关键词：
Address Affect Allergic Animal Testing Animals Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibody Formation Area Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes BCL10 gene Biochemical Biochemical Genetics C Type Lectin Receptors C-Type Lectins Cells Collaborations Complex Data Defect Dendritic Cells Development Diabetes Mellitus Disease Enzymes Functional disorder Generations Genetic Goals Hematopoietic Human Hyperactive behavior ITGAX gene Immune Immune Cell Activation Immune Complex Glomerulonephritis Immune Tolerance Immune response Immune signaling Immunity Immunoglobulin G Immunoglobulin M In Vitro Infection Inflammation Inflammatory Interleukin-1 Intestines Investigation Knock-out Lead Lupus Lymphocyte Lymphocyte Subset Lymphoid Mediating Methods Modeling Molecular Mouse Strains Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mus Mutant Strains Mice Mutation Myeloid Cells Onset of illness Organism Pathogenesis Pathway interactions Patients Permeability Phenotype Phosphotransferases Play Process Production Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Recruitment Activity Regulation Role Series Signal Pathway Signal Transduction Stromal Cells Supplementation Symbiosis T-Lymphocyte Testing Therapeutic Trials Tissues Work autoreactivity cell type chemical genetics cytokine disease phenotype experimental study genetic approach gut microbiota immunoregulation lupus-like lymph nodes microbiome microbiota mortality mouse model mutant novel protein complex public health relevance receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): There is a growing recognition that innate immune cells play a critical role in initiating and sustaining autoimmune and inflammatory disorders. The Lyn tyrosine kinase is one of the primary inhibitory enzymes that regulate innate immune cell signaling. Lyn functions by phosphorylating inhibitory receptors that recruit tyrosine phosphatases to down modulate cellular activation. In the absence of Lyn kinase, mice develop spontaneous autoimmunity resembling human systemic lupus erythematous (SLE). In preliminary studies, we have found that loss of Lyn kinase in dendritic cells (DCs) alone is sufficient to cause a severe autoimmune/inflammatory disease, with strong tissue inflammation and reduced survival, compared to the global lyn-/- mice. This disease is completely dependent on MyD88-signaling, since generation of mice lacking MyD88 and Lyn in DCs alone lack the inflammation and autoimmunity. These observations provide a clear example that mutations resulting in loss of inhibitory signaling in DCs can result in breakdown of immune tolerance in lymphocytes, leading to autoimmunity. This proposal consists of 4 specific aims. Our first aim is to define the molecular mechanisms by which inhibition of tyrosine kinase pathways impacts MyD88 signaling in DCs. We hypothesize that the cross talk between these pathways occurs via the CARD9/Malt1/Bcl10 complex, which we will investigate biochemically and genetically. We will use a chemical genetic approach to define the molecular substrates of Lyn in DCs. Aim #2 will expand on our preliminary observations, done with Dr. Lynch (UCSF) that loss of Lyn in DCs results in dysbiosis of gut microbiota, allowing for outgrowth of species that may drive systemic inflammation by altering the intestinal barrier function. We will expand on these observations in a series of microbiota profiling experiments, by use of bacterial supplementation methods, and by directly examining intestinal barrier function in the various Lyn-deficient strains. Aim #3 will expand on preliminary data suggesting that an undefined Lyn-mediated signaling pathway in non- hematopoietic cells may have an immunomodulatory effect on the disease process in lyn-/- mice. Lyn related inhibitory signaling in non-hematopoietic cells is very poorly studied. We will focus on follicular retricular cells using biochemical and genetic means (including generating mutant mice lacking Lyn in these cells specifically). Aim #4 will expand on preliminary studies done with Dr. Locksley (UCSF) showing that group 2 innate lymphocytes (ILC2s) are expanded and activated in lyn-/- mice. This aim will address whether altered signaling in ILC2 cells alone can lead to spontaneous disease phenotypes (by generating novel ILC2-specific lyn mutants) and whether these cells may contribute to autoimmune disease. Since changes in Lyn kinase related signaling pathways have been observed in human SLE patients and Lyn is now a therapeutic target in diabetes treatments (therapeutic trials) understanding the inhibitory signaling pathways regulated by this kinase in innate cells will have direct impact on human autoimmune and inflammatory conditions.