Resolution of Inflammation by the SIX-family Transcription Factors

通过六家族转录因子解决炎症

基本信息

批准号：
10553188
负责人：
Neal Mathew Alto
金额：
$ 41万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553188
关键词：
Acute Adaptive Immune System Address Adult B-Lymphocytes Bacterial Infections Biochemical Biochemistry Biological Biological Process Cell Differentiation process Cell Lineage Cell Maturation Cells ChIP-seq Chronic Communicable Diseases Complex Cytoprotection Dangerousness Data Development Developmental Gene Enterobacteria phage P1 Cre recombinase Environment Evaluation Event Exposure to Family Functional disorder Gatekeeping Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Glean Goals Gram-Negative Bacterial Infections Hematopoietic Homeobox Homeodomain Proteins Human Human Biology IL8 gene Immune Immune system Immunologics Immunology In Vitro Infection Inflammation Inflammatory Inflammatory Response Innate Immune System Knockout Mice Link LoxP-flanked allele Lymphoid Mammals Mediating Modeling Modernization Molecular Morbidity - disease rate Mus NF-kappa B NFKB Signaling Pathway Organ Organism Organogenesis Osteoclasts Pathogenicity Pathway interactions Pattern Physiological Play Pluripotent Stem Cells Proteins Regulation Regulatory Pathway Resolution Role Signal Pathway Signal Transduction Site Stress System TNF gene Testing Therapeutic Intervention Tissues Transgenic Mice Work cell type chemokine chronic inflammatory disease combat cytokine design gene function gene network genetic corepressor genome-wide human disease immune activation immune system function in vivo inhibitor innovation insight microbial model organism mouse model new therapeutic target novel novel therapeutics pathogen pathogenic bacteria pathogenic microbe persistent bacterial infection programs promoter protein activation protein expression protein function reconstitution recruit response tissue injury transcription factor transcriptome sequencing

项目摘要

Project Summary The present study focuses on our discovery that developmentally silenced SIX-family transcription factors are reactivated by TNF-family cytokines and potently suppress gene expression programs induced by non-canonical NF-kB. By first characterizing the human cytokines and pathogen associated molecular patterns (PAMPs) that induce Six1 and Six2 protein expression and by then investigating the molecular components required for their reactivation (Aim 1), these studies will reveal a new pathway for non-canonical NF-kB regulation in the mammalian immune system. Second, we will determine how Six-proteins inhibit inflammatory gene expression programs through promoter proximal mechanisms (Aim 2). Physiological significance of inflammatory resolution by Six-proteins while be investigated in mammalian model organisms using three complementary mouse models of Six1 protein function (Aim 3). Insights gleaned from these studies will explain how non-canonical NF- kB is regulated at gene promoters and will also reveal co-repressor complexes that play important roles in the inflammatory response to microbial pathogens. Developing new drugs that interfere with the ability of SIX proteins to regulate non-canonical NF-kB during microbial infection would be an innovative approach to combat human disease associated with NF-kB signaling dysfunction including chronic inflammation. Therefore, by revealing molecular details of SIX-protein function in the mammalian immune system, from biochemistry to mouse models of infection, we will uncover sites of potential weakness that may be exploited for therapeutic intervention. Importantly, these studies will also provide new insights into the pathogenic mechanisms of an important infectious disease-causing agent and also into the biology of the human inflammatory response.

项目概要本研究的重点是我们发现发育上沉默了六个家族的转录因子被 TNF 家族细胞因子重新激活并有效抑制基因表达程序由非典型 NF-kB 诱导。首先表征人类细胞因子和病原体诱导 Six1 和 Six2 蛋白表达的相关分子模式 (PAMP)，然后研究其重新激活所需的分子成分（目标 1），这些研究将揭示了哺乳动物免疫系统中非典型 NF-kB 调节的新途径。第二，我们将确定六种蛋白如何通过启动子抑制炎症基因表达程序近端机制（目标 2）。六种蛋白质消退炎症的生理意义同时使用三种互补的小鼠模型在哺乳动物模型生物体中进行研究 Six1 蛋白质功能（目标 3）。从这些研究中收集到的见解将解释非典型的 NF- kB 在基因启动子处受到调节，并且还将揭示发挥重要作用的共阻遏物复合物在对微生物病原体的炎症反应中发挥作用。开发干扰的新药物六种蛋白质在微生物感染期间调节非经典 NF-kB 的能力将是对抗与 NF-kB 信号传导功能障碍相关的人类疾病的创新方法，包括慢性炎症。因此，通过揭示六种蛋白质功能的分子细节哺乳动物的免疫系统，从生物化学到小鼠感染模型，我们将揭开免疫系统的位点可用于治疗干预的潜在弱点。重要的是，这些研究将还为重要传染病的致病机制提供了新的见解剂，也涉及人类炎症反应的生物学。