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Regulation of Macrophage Activation and Inflammation in Scleroderma

硬皮病中巨噬细胞活化和炎症的调节

基本信息

批准号：
9038599
负责人：
Patricia A. Pioli
金额：
$ 8.1万
依托单位：
DARTMOUTH COLLEGE
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：
2016-02-10 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038599
关键词：
Affect Autoimmune Diseases Automobile Driving Blood Vessels Characteristics Complex Cytokine Gene DNA Binding Development Disease Disease Progression Ensure Etiology Fibrosis Functional disorder Gene Expression Genes Genetic Polymorphism Genetic Risk Goals Human Immune Inflammation Inflammatory Inflammatory Response Injury Knowledge Macrophage Activation MicroRNAs Nuclear Pathogenesis Pathway interactions Patients Play Production Receptor Signaling Regulation Reporting Research Role Scleroderma Signal Pathway Signal Transduction Signal Transduction Pathway Skin Steroid Receptors Systemic Scleroderma Testing Therapeutic Transcriptional Activation Vascular Diseases alternative treatment combat cytokine immune activation macrophage microbial monocyte novel patient subsets public health relevance pulmonary arterial hypertension research study response targeted treatment therapy development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Scleroderma is an autoimmune disease associated with vascular injury, fibrosis, and inflammation. There is no known cure for scleroderma and current treatments are limited. Progress in the development of therapies to combat scleroderma has been hampered by a lack of knowledge of the pathophysiology that underlies this disease. We recently reported that miR-125b, a microRNA aberrantly expressed in scleroderma patients, regulates activation of NFκB. NFκB is a master regulator of pro-inflammatory cytokines associated with disease activity in scleroderma. We hypothesize that aberrant regulation of miR-125b in scleroderma MØs leads to enhanced activation of NFκB and pro-inflammatory cytokine production. The goal of this proposal is to determine how activation of NFκB is dysregulated in scleroderma macrophages and to evaluate how modulation of miR-125b alters inflammation associated with this disease. We propose to test the following hypotheses: 1. That NFκB activation differs between MØs derived from scleroderma patients vs. healthy controls. Activation of NFκB contributes to pro-inflammatory cytokine production characteristic of scleroderma. Experiments in this aim will elucidate effects on transcriptional activation, DNA binding activity and localization of components of the NFκB signaling complex. 2. That aberrant expression of miR-125b results in inappropriate activation of NFκB in scleroderma MØs. Our studies have shown that miR-125b enhances expression of κB-Ras2, a negative regulator of NFκB signaling. Aberrant expression of miR-125b has been reported in scleroderma patients. We will assess how aberrant expression of miR-125b in MØs derived from scleroderma patients affects NFκB activation and pro-inflammatory cytokine production.