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: 10265391
• 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/10265391
• 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; heme oxygenase-1; hospitalization rates; hypoxia inducible factor 1; improved; infection risk; inflammatory disease of the intestine; interest; intestinal epithelium; macrophage; military veteran; 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，有重要的 有兴趣识别肠粘膜中内源性稳态途径。这些目标激活 粘膜途径可能会恢复体内稳态，同时避免系统性的风险 经常用于控制IBD的免疫抑制。血红素氧酶-1（HO-1）及其代谢 在氧化应激的情况下激活副产品一氧化碳。刺激该途径具有 被证明在IBD的几种鼠模型中受到保护。 HO-1途径的激活 巨噬细胞已显示可增强细菌杀死和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的抗炎作用 HO-1。缺氧诱导因子（HIF）是在缺氧应激的情况下激活的转录因子。 上皮HIF的稳定受到保护，以防止肠炎。它是HO-的转录激活因子 1但是，HIF和HO-1在慢性炎症中受保护的影响之间的关系尚未 以前已建立，在肠道中也没有检查两者之间的调节关系 上皮细胞或巨噬细胞。拟议的项目将检验HIF稳定的假设 通过诱导HO-1，可以保护肠上皮细胞和Mφ免受肠道注射。基于 在我们的初步数据上，这是通过以下目标来追求的：1。定义HO-1对 上皮HIF在粘膜炎症中的保护作用。 2。确定髓样HIF是否受到保护 通过HO-1肠炎。 3。测试选择性诱导HIF/HO-1的效率以改善 慢性肠炎。这个拟议的项目是支持候选人职业的计划的一部分 通过适当的结构化发展成一个独立资助的基于VA的，基于VA的身体科学家 研究，培训和心理活动的结合。候选人是一名胃肠病学家 在粘膜免疫系统的IBD和稳态途径上。在该奖项的支持下，一个全国性的 公认的研究机构和经验丰富的导师，该项目将提高综合的专业知识 粘膜生物学和理论上的粘膜抗炎途径调制 治疗IBD。