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: 10552610
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552610
• 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; Cytoprotection; Data; Development; Disease; Drug Combinations; Enteral; Enzymes; 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; Macrophage; Malignant Neoplasms; Measures; Mentors; Metabolic; Modeling; Mucosal Immune System; Mucositis; Mucous Membrane; Mus; Myelogenous; Oxidative Stress; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Predisposition; Procollagen-Proline Dioxygenase; Protein Isoforms; Regulation; Research; Risk; Role; Scientist; Signal Transduction; Stimulus; Stress; Structure; Testing; Therapeutic; Time; Tissues; Training; Transcription Coactivator; Translating; Translations; Veterans; bHLH-PAS factor HLF; 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; 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.

肠粘膜炎症和稳态信号之间复杂平衡的破坏