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Attenuation of Lupus by Foxo3

Foxo3 减弱狼疮作用

基本信息

批准号：
9113494
负责人：
Anne B Satterthwaite
金额：
$ 17.81万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2015-07-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113494
关键词：
1-Phosphatidylinositol 3-Kinase Anti-Inflammatory Agents Anti-inflammatory Antibody Formation Antigen-Antibody Complex Antigens Apoptosis Apoptotic Attenuated Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Assay Biological Markers Cell Lineage Cells Clinical Complex Coupled Crohn&apos s disease Data Dendritic Cells Development Diagnostic Disease Event Family Feedback Future Gene Expression Gene Expression Profile Genes Genetic Models Genetic Polymorphism Genetic Recombination Health Human Hyperactive behavior Immune Immune Tolerance Immune system Individual Inflammation Inflammatory Inflammatory Response Interferon Type I Interferons Lupus Measures Mediating Messenger RNA Mining Modeling Molecular Molecular Profiling Mus Myelogenous Myeloid Cells Nuclear Nuclear Antigens Nucleic Acids Organ Pathogenesis Patients Phenotype Play Predisposition Process Production Prognostic Marker Receptors, Antigen, B-Cell Rheumatoid Arthritis Role Severities Signal Transduction Specificity Systemic Lupus Erythematosus Testing Therapeutic Uses Tissues Toll-like receptors Transgenic Model Work attenuation autoreactive B cell autoreactivity base cell type cytokine diagnostic biomarker falls genetic signature lupus-like mRNA Expression macrophage member monocyte new therapeutic target novel novel therapeutic intervention prevent prognostic tool receptor response transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): The autoimmune disease Systemic Lupus Erythematosus (SLE) is characterized by a loss of tolerance to nu- clear antigens and the production of autoantibodies. These form immune complexes which promote inflammation and tissue damage. Several lines of evidence suggest that SLE pathogenesis is mediated by loss of adaptive immune tolerance coupled with hyperactivity of the innate immune system. The latter is associated with increased production of pro-inflammatory cytokines, including type I IFNs. Defining the molecular mechanisms that control these events may reveal novel therapeutic targets for SLE. We hypothesize that the transcription factor Foxo3 serves to attenuate the severity of lupus. Foxo3 is a member of the Foxo family of transcription factors which are downregulated by PI3 kinase signaling at both the mRNA and posttranslational levels. Our preliminary data indicate that Foxo3-deficient mice have altered immature B cell apoptosis and receptor editing, both means of central B cell tolerance. Foxo3 also has several unique anti-inflammatory roles in myeloid lineage cells. It dampens proinflammatory responses in dendritic cells and is known to limit the expression of type I IFNs and IFN signature genes in both human and murine macrophages. Elevated Foxo3 mRNA expression is associated with reduced severity of Crohn's disease and rheumatoid arthritis, and tumor- infiltrating dendritic cells are tolerogenic due to increased Foxo3 mRNA expression. This highlights the importance of Foxo3, and the control of its mRNA expression, in modulating inflammatory responses. Interestingly, preliminary analysis suggests that SLE patients fall into two distinct groups with respect to mRNA expression of Foxo3 and a cluster of associated genes (which we term the "Foxo3 signature"). Here, we will test the hypothesis that Foxo3 plays a protective role in lupus via the following Aims. In Aim 1, we will ask whether B cells that remain autoreactive after extensive BCR editing survive rather than undergo deletion in the absence of Foxo3. We will study editing and deletion in Foxo3-/- mice using a PCR assay of RS recombination, a measure of receptor editing, and an Ig Tg model in which autoreactive B cells are deleted. In Aim 2, we will determine whether mice that are prone to develop lupus have more severe disease in the absence of Foxo3, and if so which cell types mediate this effect. In Aim 3, we will compare SLE patients expressing low vs. high levels of Foxo3 for gene expression profiles and clinical disease parameters to determine whether patients with high levels of Foxo3 and associated "signature" genes have an altered disease course. This work will deter- mine whether Foxo3 limits the severity of lupus and characterize a unique set of Foxo3 associated biomarkers for a subset of SLE patients. These studies will also pave the way for new therapeutic approaches that target Foxo3 or Foxo3 signature genes.