Factors Contributing to Wound Healing in the Colon

有助于结肠伤口愈合的因素

• 批准号: 7976946
• 负责人: BETH B MCCONNELL
• 金额: $ 7.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976946
• 关键词: Address; Area; Bacterial Infections; Biochemical; Biological Assay; Blood Vessels; Cardiovascular Models; Cell physiology; Chemicals; Chronic; Colitis; Colon; Data; Development; Dietary intake; Disease; Ectopic Expression; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Exhibits; Exposure to; Family; Flare; Funding; Gene Targeting; Genes; Grant; Healed; In Vitro; Infectious Agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestines; Investigation; Irritants; Knock-out; Kruppel-like transcription factors; Lesion; Mediating; Microarray Analysis; Modeling; Mucositis; Mucous Membrane; Mus; Organism; Patients; Pharmaceutical Preparations; Process; Proliferating; Receptor Signaling; Regulation; Reporting; Role; Site; Small Interfering RNA; Sodium Dextran Sulfate; Stimulus; Stress; Testing; Tissues; Toxin; Ulcer; Wild Type Mouse; Wound Healing; base; biological adaptation to stress; colon cancer cell line; enteric pathogen; gastrointestinal; healing; in vivo; intestinal epithelium; member; migration; mouse model; novel; pathogenic bacteria; public health relevance; repaired; research study; response; response to injury; restoration; stressor; therapeutic target; tool; transcription factor; villin

DESCRIPTION (provided by applicant): The intestinal epithelium forms a dynamic barrier between the organism and various external factors present within the lumen, including commensal and pathogenic bacteria, dietary intake, gastrointestinal secretions and drugs. In inflammatory bowel disease (IBD), the epithelial barrier is repeatedly disrupted during flares of inflammation, allowing for increased exposure to infectious agents and toxins that exacerbate the existing inflammatory condition. Thus, rapid repair of epithelial breeches is critical for limiting mucosal inflammation and healing ulcerated lesions in these patients. Kruppel-like factor 5 (KLF5) is a member of a family of transcription factors that function in the regulation of diverse cellular processes, including development, proliferation and differentiation. KLF5 is highly expressed in epithelial cells in proliferating regions of the gut, and has been shown to be activated by a number of stress stimuli, including exposure to bacterial components and injury. In this proposal, we provide preliminary data that KLF5 is activated in epithelial cells at ulcer margins in the colon following injury with the chemical irritant, dextran sodium sulfate (DSS). Furthermore, mice with heterozygous expression of Klf5 (Klf5) exhibit increased sensitivity to DSS and show reduced expression of the wound healing marker, EGFR and reduced migration of epithelial cells to restore the epithelial barrier at ulcer margins. Based on these results, we hypothesize that KLF5 promotes the healing of damaged intestinal tissues through activation of gene targets that enhance restoration of the epithelial barrier. To test this hypothesis, two Specific Aims have been proposed: (I) to use an intestinal specific Klf5 conditional knockout as a definitive model for examining the role of KLF5 in epithelial restitution and wound healing and (II) to identify targets of KLF5 that are important for epithelial migration and wound repair using in vitro manipulation of KLF5 expression and wounding assays. By identifying factors necessary for epithelial restitution, we can provide potential therapeutic targets for enhancing wound healing in IBD patients. PUBLIC HEALTH RELEVANCE: One of the major complications of inflammatory bowel disease (IBD) is chronic disruption of the intestinal epithelium which exacerbates and prolongs the disease. Understanding how the mucosa is repaired and identifying key molecules involved in restitution of the epithelial barrier can provide potential therapeutic targets directed at mucosal healing for IBD patients.

描述（由申请人提供）：肠上皮形成了生物体与管腔中存在的各种外部因素之间的动态障碍，包括共生和致病细菌，饮食摄入，胃肠道分泌和药物。在炎症性肠病（IBD）中，上皮屏障在炎症期间反复中断，从而增加了加剧现有炎症状况的传染剂和毒素的暴露。因此，上皮马裤的快速修复对于限制这些患者的粘膜炎症和愈合溃疡病变至关重要。 Kruppel样因子5（KLF5）是在调节各种细胞过程（包括发育，增殖和分化）中起作用的转录因子家族的成员。 KLF5在肠道增殖区域的上皮细胞中高度表达，并且已被证明被许多应力刺激激活，包括暴露于细菌成分和损伤。在此提案中，我们提供了初步数据，即用化学刺激剂硫酸葡萄糖（DSS）损伤后，在结肠溃疡的上皮细胞中激活KLF5。此外，具有KLF5（KLF5）杂合表达的小鼠对DSS的敏感性提高，并且显示了伤口愈合标记物，EGFR的表达降低，EGFR和上皮细胞的迁移降低，以恢复溃疡边缘处的上皮屏障。基于这些结果，我们假设KLF5通过激活基因靶标促进受损的肠道组织的愈合，从而增强上皮屏障的恢复。为了检验这一假设，已经提出了两个具体目标：（i）使用肠道特异性的KLF5有条件敲除作为检验KLF5在上皮恢复和伤口愈合中的作用的确定模型，以及（ii）来识别KLF5的靶标，这些靶标识别对上皮迁移和伤口修复Klf5表达和伤口的klf5表现和伤口表达和伤口的表现和伤口表达和伤口。通过确定上皮恢复所需的因素，我们可以提供潜在的治疗靶标，以增强IBD患者的伤口愈合。 公共卫生相关性：炎症性肠病（IBD）的主要并发症之一是肠道上皮的慢性破坏，加剧并延长了疾病。了解如何修复粘膜并识别涉及恢复上皮屏障的关键分子可以为IBD患者提供针对粘膜愈合的潜在治疗靶标。