Therapeutic Potential of Targeted Mucosal Heme Oxygenase-1 in Colitis

靶向粘膜血红素加氧酶 1 在结肠炎中的治疗潜力

• 批准号: 9906044
• 负责人: Joseph Onyiah
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906044
• 关键词: Address; Adoptive Transfer; Age; Animal Model; Anti-Inflammatory Agents; Award; Biliverdine; Biochemical; Biological; Biology; Bone Marrow; Carbon Monoxide; Cells; Chronic; Clinical; Colitis; Complex; Data; Development; Disease; Drug Combinations; Enteral; Enzymes; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Funding; Gastroenterologist; Heme; Homeostasis; Hospitalization; Human; Hypoxia; Hypoxia Inducible Factor; Immunosuppression; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Institution; Interleukin-10; Intestinal Mucosa; Iron; Knock-out; Link; Malignant Neoplasms; Measures; Mentors; Metabolic; Modeling; Mucosal Immune System; Mucositis; Mucous Membrane; Mus; Myelogenous; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Population; Procollagen-Proline Dioxygenase; Protein Isoforms; Regulation; Research; Research Training; Risk; Role; Scientist; Signal Transduction; Stimulus; Stress; Structure; Testing; Therapeutic; Time; Tissues; Transcription Coactivator; Translating; Translations; Veterans; bHLH-PAS factor HLF; base; career development; chemokine; cost; cytokine; defined contribution; design; dimer; disorder control; efficacy testing; experience; gene repression; heme oxygenase-1; hospitalization rates; hypoxia inducible factor 1; improved; infection risk; inflammatory disease of the intestine; interest; intestinal epithelium; macrophage; mouse model; novel; novel strategies; older patient; response; therapeutic target; transcription factor

Disruptions in the complex balance between inflammatory and homeostatic signaling in the intestinal mucosa can result in diseases such as inflammatory bowel disease (IBD). From this perspective, there is significant interest in identifying endogenous homeostatic pathways in the intestinal mucosa. Targeted activation of these mucosal pathways may restore homeostasis and at the same time avoid the risks of systemic immunosuppression which is frequently utilized for control of IBD. Heme oxygenase-1 (HO-1) and its metabolic by-product carbon monoxide are activated in the setting of oxidative stress. Stimulation of this pathway has been demonstrated to be protective in several murine models of IBD. Activation of the HO-1 pathway in macrophages has been shown to augment bacterial killing and negatively regulate proinflammatory cytokine expression in the intestinal mucosa. We have also identified an anti-inflammatory role for intestinal epithelial HO-1. Hypoxia inducible factor (HIF) is a transcription factor that is activated in the setting of hypoxic stress. Stabilization of epithelial HIF is protective against intestinal inflammation. It is a transcriptional activator of HO- 1 but a relationship between the protective impact of HIF and HO-1 in chronic intestinal inflammation has not previously been established, nor has the regulatory relationship between the two been examined in intestinal epithelial cells or macrophages. The proposed project will test the hypothesis that stabilization of HIF in intestinal epithelial cells and MΦ is protective against intestinal inflammation through induction of HO-1. Based on our preliminary data, this is pursued with the following objectives: 1. Define the contribution of HO-1 to the protective impact of epithelial HIF in mucosal inflammation. 2. Determine if myeloid HIF is protective against intestinal inflammation through HO-1. 3. Test the efficacy of selective induction of HIF/HO-1 for amelioration of chronic intestinal inflammation. This proposed project is part of a plan to support the Candidate's career development into an independently funded, VA-based, physician-scientist through an appropriately structured combination of research, training and mentoring activities. The Candidate is a gastroenterologist with a focus on IBD and homeostatic pathways of the mucosal immune system. With the support of this award, a nationally recognized research institution, and experienced mentors, this project will advance expertise in integrated mucosal biology and proficiency in therapeutic modulation of mucosal anti-inflammatory pathways for treatment of IBD.

肠粘膜中炎症和稳态信号之间复杂平衡的破坏 可能导致炎症性肠病（IBD）等疾病。从这个角度来看， 对确定肠粘膜中内源性稳态途径的兴趣。有针对性地激活这些 粘膜途径可以恢复体内平衡，同时避免全身性疾病的风险。 通常用于控制IBD的免疫抑制剂。血红素加氧酶-1（HO-1）及其代谢 副产物一氧化碳在氧化应激的情况下被活化。刺激这一途径， 在几种IBD小鼠模型中证明具有保护作用。HO-1通路的激活 巨噬细胞已显示出增强细菌杀伤并负调节促炎细胞因子 在肠粘膜中的表达。我们还确定了肠上皮细胞的抗炎作用， HO-1缺氧诱导因子（Hypoxia inducible factor，HIF）是一种在缺氧应激时被激活的转录因子。 稳定的上皮缺氧诱导因子对肠道炎症有保护作用。它是HO-1的转录激活因子。 1，但HIF和HO-1在慢性肠道炎症中的保护作用之间的关系尚未得到证实。 以前已经建立，也没有在肠道中检查两者之间的调节关系 上皮细胞或巨噬细胞。拟议的项目将测试这一假设，即稳定缺氧诱导因子， 肠上皮细胞和MΦ通过诱导HO-1对肠道炎症具有保护作用。基于 根据我们的初步数据，这一工作的目标如下：1。确定HO-1对 上皮HIF在粘膜炎症中的保护作用。2.确定髓样HIF是否具有保护作用， 肠道炎症通过HO-1。3.测试选择性诱导缺氧诱导因子/HO-1改善缺氧的功效 慢性肠道炎症本项目是支持候选人职业生涯计划的一部分 发展成为一个独立资助，VA为基础，通过适当的结构， 研究、培训和指导活动相结合。候选人是一名胃肠病学家， IBD和粘膜免疫系统的稳态途径。在该奖项的支持下，全国范围内 公认的研究机构和经验丰富的导师，该项目将推进专业知识的综合 粘膜生物学和粘膜抗炎途径的治疗调节的熟练程度， IBD的治疗