Defensins and Corneal Wound Healing

防御素和角膜伤口愈合

• 批准号: 7473802
• 负责人: ALISON M MCDERMOTT
• 金额: $ 24.73万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473802
• 关键词: Address; Animal Model; Animals; Antisense Oligonucleotides; Biological Assay; CAP18 lipopolysaccharide-binding protein; Cells; Code; Competitive Binding; Cornea; Corneal Injury; Data; Defensins; Effectiveness; Epithelial Cells; Gene Expression; Genes; Healed; Homologous Gene; Human; In Vitro; Infection; Injury; Interleukin-6; Knock-out; Knockout Mice; Lead; Mediating; Modeling; Monitor; Mus; Optics; Organ Culture Techniques; Peptides; Predisposition; Process; Production; Property; Pseudomonas; Pseudomonas aeruginosa; Rate; Rattus; Research Personnel; Rodent; Role; Signaling Molecule; Small Interfering RNA; Sodium Chloride; Testing; Therapeutic Agents; Wound Healing; antimicrobial; beta-defensin-2; cathelicidin; cell motility; corneal epithelium; cytokine; fMet-Leu-Phe receptor; healing; homologous recombination; in vivo; inhibitor/antagonist; insight; killings; migration; ocular surface; pathogen; programs; receptor; repaired; response; restoration

DESCRIPTION: Damage to the corneal epithelium renders the cornea vulnerable to infection and compromises its optical functions. Rapid repair is critical. Much remains unknown of how repair is regulated but multifunctional molecules that accelerate wound healing and protect against infection are likely to be particularly important and have great potential as exogenously applied therapeutic agents. After injury the corneal epithelium expresses human beta-defensin-2 (hBD-2). Our preliminary data also indicate that expression of the cathelicidin LL-37 is upregulated. hBD- 2 and LL-37 are peptides with antimicrobial activity capable of stimulating migration and proliferation of various human cells. Thus, they are uniquely placed to promote healing and provide protection against infection at the ocular surface. The following general hypothesis is proposed : hBD-2, LL-37 and their rodent homologues, are multifunctional molecules which promote ocular surface wound healing and protect against infection. Cultured human corneal epithelial cells, human corneas in organ culture, ocular pathogens and animal models will be used to address the following specific aims: Specific Aim 1 : Hypothesis : LL-37 is upregulated by cytokines after injury and stimulates corneal epithelial cell migration, proliferation and cytokine secretion via formyl peptide receptor-like 1 (FPRL1). Specific Aim 2 : Hypothesis : Animal models in which the rodent homologues of hBD-2 and LL-37 have been eliminated show impaired corneal epithelial healing in vivo. Specific Aim 3 : Hypothesis : beta-Defensin-2 and cathelicidin are effective against ocular pathogens in vitro and mice in which the hBD-2/LL-37 homologues have been knocked out show increased susceptibility to P. aeruginosa. These studies will help delineate the roles of defensins and cathelicidin at the ocular surface and will provide valuable insight in to their potential as therapeutic agents.

描述：对角膜上皮的损害使角膜容易受到感染的影响，并损害其光学功能。快速维修至关重要。对于如何调节修复，但多功能分子加速伤口愈合并防止感染的多功能分子可能尤其重要，并且作为外源应用治疗剂具有很大的潜力。损伤后，角膜上皮表达人β-防御素-2（HBD-2）。我们的初步数据还表明，Cathelicidin LL-37的表达上调。 HBD-2和LL-37是具有抗菌活性的肽，能够刺激各种人类细胞的迁移和增殖。因此，它们是独特的，以促进愈合并提供防止眼表面感染的保护。提出了以下一般假设：HBD-2，LL-37及其啮齿动物同源物是多功能分子，可促进眼表面伤口愈合并预防感染。培养的人角膜上皮细胞，器官培养中的人角膜，眼部病原体和动物模型将用于解决以下特定目的：特定目标1：假设：LL-37在受伤后被细胞因子上调，并刺激角膜上皮细胞迁移，增殖，增殖和细胞因子通过emlyl pleptide ppleptide受体受体分泌。 特定目的2：假设：已经消除了HBD-2和LL-37的啮齿动物同源物的动物模型，显示体内角膜上皮愈合受损。 特定目标3：假设：β-二芬蛋白-2和cathelicidin在体外和小鼠中有效地针对眼病原体，其中HBD-2/LL-37同源物被敲出，显示出对铜绿假单胞菌的敏感性增加。 这些研究将有助于描述防御素和cathelicidin在眼表面的作用，并为其作为治疗剂的潜力提供宝贵的见解。