INTESTINAL EPITHELIAL WOUND HEALING: NSAIDS AND CALPAIN INHIBITION

肠上皮伤口愈合：NSAIDS 和钙蛋白酶抑制

• 批准号: 7959796
• 负责人: JAMES D LILLICH
• 金额: $ 18.25万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959796
• 关键词: Attention; Calpain; Cardiovascular system; Cell Migration Inhibition function; Chronic; Computer Retrieval of Information on Scientific Projects Database; Cysteine Protease; Data; Disease; Drug toxicity; Elements; Epithelial; Epithelial Cells; Event; Funding; Gene Expression; Goals; Grant; Health; Health Personnel; Human; Hydrophobicity; Incidence; Inflammatory; Institution; Intestines; Investigation; Knowledge; Link; Mediating; Neutrophil Infiltration; Oral; Pathway interactions; Pharmaceutical Preparations; Prevention; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Research; Research Personnel; Resources; Rofecoxib; Scientist; Source; Staging; Stomach; Surface; Ulcer; United States National Institutes of Health; Wound Healing; calpastatin; celecoxib; cell motility; design; gastrointestinal; improved; inhibitor/antagonist; migration; neutrophil; novel strategies; research study; response; wound

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goals of this project are to elucidate mechanisms that mediate non-steroidal anti-inflammtory drugs (NSAIDs) effects on cell migration during wound healing, and use the knowledge gained to develop novel strategies for treatment and prevention of gastrointestinal (GI) ulcers. Adverse GI effects of NSAIDs in humans and other species include oral, gastric, duodenal, and colonic ulceration. Despite extensive investigation, the mechanisms responsible for NSAID-associated GI damage are not completely understood. NSAIDs may promote ulcer formation, not only by inhibiting mucosal cyclooxygenase (COX) and decreasing cytoprotective prostaglandins (PG), but also by adversely influencing intestinal microflora, neutrophil recruitment, surface hydrophobicity and epithelial restitution. Recent evidence suggests that calpains (cysteine proteases) are vital to the several key pathways of fibroblastic and WBC migration. Our preliminary data indicate that ulcerogenic NSAIDs either down-regulate calpain gene expression or up-regulate the constituent inhibitor, calpastatin. From a global perspective this has led us to hypothesyze that the formation of NSAID-induced GI ulceration is due, in part, to inhibited epithelial and fibroblastic cell migration, facilitated neutrophil migration into the wound, leading to an uncoupled and uncoordinated wound healing response setting the stage for a chronic inflammatory state. The experiments proposed here are designed specifically to link NSAID inhibition of cell migration with NSAID effects on events vital to calpain function within differentiated intestinal epithelial cells (IECs). The specific aims of this project are to: 1) Demonstrate that calpains are critical to normal IEC migration. 2)Confirm that calpains are a target for NSAID-toxicity and disruption of intestinal epithelial wound healing. 3) Determine the effects of NSAIDs on the downstream substrates of the calpains, specifically cytoskeletal and intregin elements required during intestinal epithelial restitution. The results of this project will provide valuable data immediately useful not only to the health care providers who want to make rational decisions about prescribing NSAIDs, but also to the industrial scientists who strive to develop less toxic alternatives to the drugs currently available. Escalating concerns about serious cardiovascular complications linked to celecoxib and rofecoxib, the NSAIDs associated with lowest incidence of drug-induced gastropathy, draw attention to the urgent need for improved understanding of the mechanisms that underlie NSAID-induced ulcers.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的长期目标是阐明非类固醇抗炎药(NSAIDs)在伤口愈合过程中对细胞迁移的调节机制，并利用所获得的知识开发治疗和预防胃肠道(GI)溃疡的新策略。非甾体抗炎药对人类和其他物种的不良胃肠道影响包括口腔、胃、十二指肠和结肠溃疡。尽管进行了广泛的调查，但非甾体抗炎药相关的胃肠道损伤的机制尚未完全了解。非甾体抗炎药可促进溃疡的形成，不仅通过抑制粘膜环氧合酶(COX)和减少细胞保护性前列腺素(PG)，还通过对肠道微生物区系、中性粒细胞募集、表面疏水性和上皮修复产生不利影响。最近的证据表明，钙蛋白酶(半胱氨酸蛋白酶)在成纤维细胞和白细胞迁移的几个关键途径中至关重要。我们的初步数据表明，溃疡性非类固醇抗炎药要么下调calain基因的表达，要么上调组成抑制剂calastatin的表达。从全球的角度来看，这使我们假设NSAID诱导的GI溃疡的形成在一定程度上是由于抑制了上皮细胞和成纤维细胞的迁移，促进了中性粒细胞向伤口的迁移，导致了一种解偶联和不协调的伤口愈合反应，为慢性炎症状态奠定了基础。这里提出的实验是专门设计的，目的是将NSAID抑制细胞迁移与NSAID对分化的肠上皮细胞(IECS)内钙蛋白功能至关重要的事件的影响联系起来。该项目的具体目标是： 1)证明钙调蛋白对正常的IEC迁移至关重要。 2)确认Calain是非甾体抗炎药毒性作用的靶点，并破坏肠上皮伤口愈合。 3)确定非类固醇抗炎药对钙调蛋白下游底物的影响，特别是肠上皮重建过程中所需的细胞骨架和整合素元素。 该项目的结果将立即提供有价值的数据，不仅对希望合理决定非类固醇抗炎药处方的医疗保健提供者有用，而且对努力开发毒性较低的现有药物替代品的工业科学家也有用。人们对与塞来昔布和罗非昔布有关的严重心血管并发症的担忧不断升级，这两种非类固醇抗炎药与药物引起的胃病的发病率最低，这促使人们注意到迫切需要更好地了解非类固醇抗炎药诱发溃疡的机制。