Roles of Glycoconjugates and Redox Signaling in Tumor Biology

糖缀合物和氧化还原信号在肿瘤生物学中的作用

基本信息

批准号：
8554030
负责人：
david d roberts
金额：
$ 42.33万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8554030
关键词：
Adverse effects Affinity Angiogenesis Inhibitors Animal Model Bacteria Binding Biological Process CD3 Antigens CD4 Positive T Lymphocytes CD44 Antigens CD44 gene Cancer Patient Cancer cell line Carbon Monoxide Cardiovascular Physiology Cardiovascular system Cell Adhesion Molecules Cell Line Cell surface Cells Cystathionine beta-Synthase Cysteine Desulfhydrase Development Diagnostic Diet Dose Enzymes Etiology Exhibits Extracellular Matrix FDA approved Family Glycoconjugates Glycolipids Glycoproteins Hemostatic function Heparan Sulfate Proteoglycan Human Hyaluronan Hydrogen Sulfide IL2RA gene Immunologic Surveillance Inflammatory Bowel Diseases Inorganic Sulfates Interleukin-2 Intestines Knockout Mice Ligands Maintenance Mediating Mediator of activation protein Metabolic Pathway Metabolism Mitogen-Activated Protein Kinases Molecular Mus Mutant Strains Mice Neoplasm Metastasis Oxidation-Reduction Pathologic Neovascularization Pathway interactions Pharmaceutical Preparations Physiological Play Polysaccharides Production Proteins Proteoglycan Relative (related person)Role Signal Transduction Signaling Molecule Splenocyte T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Therapeutic Uses Thrombospondin 1 Thrombospondins Thymus Gland Tumor Angiogenesis Tumor Biology Tumor Tissue Ulcerative Colitis Unspecified or Sulfate Ion Sulfates Wild Type Mouse angiogenesis autocrine blood pressure regulation glycosylation inhibitor/antagonist neoplastic cell neovascularization novel prevent response small molecule sulfate reducing bacteria therapeutic angiogenesis therapeutic target thymocyte tissue culture

项目摘要

Hydrogen sulfide (H2S) is an endogenous signaling molecule that may act via protein sulfhydrylation to regulate various physiological functions. H2S is also a byproduct of dietary sulfate metabolism by gut bacteria. Inflammatory bowel diseases such as ulcerative colitis are associated with an increase in the colonization of the intestine by sulfate reducing bacteria along with an increase in H2S production. Consistent with its increased production, H2S is implicated as a mediator of ulcerative colitis both in its genesis or maintenance. As T cells are well established mediators of inflammatory bowel disease, we investigated the effect of H2S exposure on T cell activation. Using primary mouse T lymphocytes (CD3+), OT-II CD4+ T cells, and the human Jurkat T cell line, we show that physiological levels of H2S potentiate TCR-induced activation. Nanomolar levels of H2S (50-500 nM) enhance T cell activation assessed by CD69 expression, interleukin-2 expression, and CD25 levels. Exposure of T cells to H2S dose-dependently enhances TCR-stimulated proliferation with a maximum at 300 nM (30% increase, p < 0.01). Furthermore, activation increases the capacity of T cells to make H2S via increased expression of cystathionine gamma-lyase and cystathionine beta-synthase. Disrupting this response by silencing these H2S producing enzymes impairs T cell activation, and proliferation and can be rescued by the addition of 300 nM H2S. Thus, H2S represents a novel autocrine immunomodulatory molecule in T cells.