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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的长期目标是阐明介导非甾体类抗炎药（NSAIDS）对伤口愈合过程中细胞迁移的影响的机制，并利用获得的知识来制定新的策略来治疗和预防胃肠道（GI）溃疡。 NSAID在人类和其他物种中的不良GI效应包括口服，胃，十二指肠和结肠溃疡。尽管进行了广泛的调查，但尚未完全了解与NSAID相关的GI损害的机制。 NSAIDS不仅可以通过抑制粘膜环氧酶（COX）和降低细胞保护前列腺素（PG）来促进溃疡形成，还可以通过不利影响肠道微生物，中性粒细胞募集，表面疏水性和上皮恢复。最近的证据表明，CALPAIN（半胱氨酸蛋白酶）对于成纤维细胞和WBC迁移的几种关键途径至关重要。我们的初步数据表明，溃疡性NSAID会下调钙蛋白酶基因表达或上调组成抑制剂Calpastatin。 从全球的角度来看，这使我们假设NSAID诱导的胃肠道溃疡的形成部分是由于抑制上皮和成纤维细胞细胞迁移，中性粒细胞迁移到伤口中，从而促进了促进的，导致未偶联的伤口愈合响应，从而使炎症状态置于慢性病状态。此处提出的实验专门旨在将细胞迁移的NSAID抑制与NSAID对分化肠上皮细胞（IEC）中Calpain功能至关重要的事件的影响联系起来。该项目的具体目的是： 1）证明Calpain对正常IEC迁移至关重要。 2）确认钙蛋白酶是NSAID毒性和肠上皮伤口愈合的破坏的靶标。 3）确定NSAID对CALPAIN的下游底物的影响，特别是肠上皮恢复过程中所需的细胞骨架和内骨元素。 该项目的结果将立即提供有价值的数据，不仅对想要做出开处方NSAID的合理决策的医疗保健提供者有用，而且还对努力开发出对当前可用药物的毒性替代品的工业科学家也有用。对与Celecoxib和Rofecoxib相关的严重心血管并发症的担忧加剧，NSAID与药物诱发的胃病发病率最低有关，引起人们对迫切需要对基于NSAID诱发的溃疡的机制的迫切需要的关注。