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: 10438663
• 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/10438663
• 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; 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; 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; gut inflammation; heme oxygenase-1; hospitalization rates; hypoxia inducible factor 1; improved; infection risk; interest; intestinal epithelium; macrophage; military veteran; mouse model; murine colitis; 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.

肠粘膜炎性信号和稳态信号之间复杂平衡的破坏 可导致炎症性肠病(IBD)等疾病。从这个角度来看，有重要的 对确定肠粘膜内源性动态平衡途径的兴趣。定向激活这些 粘膜通路可以恢复动态平衡，同时避免全身性 免疫抑制是控制IBD的常用手段。血红素加氧酶1(HO-1)及其代谢 在氧化应激状态下，副产物一氧化碳被激活。对这条通路的刺激 已被证明在几种IBD小鼠模型中具有保护作用。血管内皮细胞HO-1通路的激活 巨噬细胞已被证明可以增强细菌杀灭和负向调节促炎细胞因子 在肠粘膜中表达。我们还确定了肠上皮细胞的抗炎作用。 HO-1。低氧诱导因子(HIF)是一种在低氧应激状态下被激活的转录因子。 上皮HIF的稳定对肠道炎症有保护作用。它是HO-的转录激活剂- 但HIF和HO-1在慢性肠炎中的保护作用之间的关系尚未见报道 两者之间的调控关系也没有在肠道中得到检验 上皮细胞或巨噬细胞。拟议的项目将检验以下假设：HIF在 肠上皮细胞和M-Φ通过诱导HO-1对肠道炎症有保护作用。基座 根据我们的初步数据，这是为了实现以下目标：1.确定HO-1对 上皮性缺氧诱导因子在黏膜炎症中的保护作用2.确定髓系缺氧诱导因子是否具有保护作用 通过HO-1引起肠道炎症。3.检测选择性诱导HIF/HO-1改善HIF/HO-1的疗效。 慢性肠炎。这个拟议的项目是支持候选人职业生涯的计划的一部分 通过适当的结构，发展成为独立资助的、以退伍军人为基础的内科科学家 研究、培训和指导活动相结合。应聘者是一位胃肠病专家，重点是 IBD和粘膜免疫系统的动态平衡途径。在这个奖项的支持下，一个全国性的 公认的研究机构，和经验丰富的导师，这个项目将促进专业知识的综合 粘膜生物学和对粘膜抗炎通路治疗调节的熟练程度 IBD的治疗。