Functions of mammalian PGLYRPs in the cornea

哺乳动物 PGLYRP 在角膜中的功能

• 批准号: 8093360
• 负责人: Shukti Chakravarti
• 金额: $ 24.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093360
• 关键词: Affect; Age; Amidohydrolases; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Biological Assay; Biology; Cell Culture Techniques; Cells; Clinical; Contact Lenses; Cornea; Corneal Injury; Debridement; Defense Mechanisms; Defensins; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Eye; Future; Genes; Healed; Health; Homeostasis; Human; Immune; Impaired wound healing; In Vitro; Infection; Inflammation; Inflammatory; Injury; Insecta; Keratitis; Knock-out; Knockout Mice; Lead; Letters; Ligands; Lung; Modeling; Molecular; Mus; Mutant Strains Mice; Natural Immunity; Nuclear; Operative Surgical Procedures; Outcome; Pathway interactions; Peptides; Peptidoglycan; Protein Family; Proteins; Pseudomonas; Pseudomonas aeruginosa; Regulation; Reporting; Research; Risk; Role; Signal Transduction; Small Interfering RNA; TLR2 gene; TLR4 gene; Testing; Therapeutic; Toll-Like Receptor 2; Transplantation; Trauma; Vision; Work; amidase; antimicrobial; antimicrobial peptide; bactericide; base; corneal epithelium; cytokine; experience; healing; improved; in vivo; killings; lumican; member; migration; mouse model; natural antimicrobial; pathogen; pathogenic bacteria; peptidoglycan recognition protein; prophylactic; receptor; response; skills; wound

DESCRIPTION (provided by applicant): The cornea is a transparent, refractive, protective mucosal barrier of the eye. Corneal infections pose a serious threat to healthy vision. Risks of infections increase with injury, surgery, daily contact lens wear and age. Research on antimicrobial proteins and peptides is critical for elucidating natural protective mechanisms in the cornea and therapies based on these. Our proposal focuses on the mammalian peptidoglycan recognition protein (PGLYRP) family of four antimicrobial proteins, which exist in various mucosal barriers, and identified just over a decade ago. We found PGLYRP1, and subsequently others PGLYRP2, -3 and -4 in the human and mouse cornea. Functions of mammalian PGLYRP members are generally underexplored, and in particular little is known of these in the eye. Much more is known of the large PGLYRP family in insects: they are mostly bactericidal, some hydrolyze peptidoglycans (PGN) to restrict inflammation, while others signal to host toll and imd pathways to induce genes of innate immunity and antimicrobial peptides (AMP). Mammalian PGLYRP1, - 3 and -4 are bactericidal against gram positive and negative bacteria, and PGLYRP2 is an amidase. In vitro, they work synergistically with AMPs, synergy in vivo is not known, but suspected. Whether the mammalian PGLYRPs also modulate innate immune signals remains to be fully investigated.. Thus, the mammalian PGLYRPs may represent a new class of antimicrobial immune modulators in the cornea. Our central hypothesis in this R21 proposal is that PGLYRPs in the mammalian cornea may have a dual role in deterring pathogenic bacterial infections while promoting innate immune signals for corneal healing and homeostasis. Two aims will test this central hypothesis.1) Test antibacterial defense capabilities of Pglyrp1-4 null mice in a Pseudomonas (P).aeruginosa keratitis model. 2a)Test if the PGLYRPs cross talk with innate immune signals (TLR2, 4 and Nod2) in the cornea to up regulate cytokines and b- defensins, and 2b) whether the PGLYRPs expedite corneal healing by promoting epithelial migration. This exploratory study of the PGLYRP family will provide the necessary assessment of its role in the cornea and the groundwork for future detailed studies of each member in promoting corneal health, curbing infections and developing targeted therapies. In the future our study may lead to prophylactic or therapeutic approaches that tweak PGLYRP levels in the corneal epithelium before/after surgery, infection and storage of transplant corneas. PUBLIC HEALTH RELEVANCE: Our findings on this peptidoglycan recognition protein family will elucidate natural antimicrobial defense mechanisms in the cornea, therapeutic/prophylactic strategies for regulating their levels and functions during corneal infections and injury or surgery-related trauma, transplant cornea or contact lens storage.

描述（由申请人提供）：角膜是眼睛的透明，折射，保护性粘膜屏障。角膜感染对健康的视力构成了严重威胁。感染风险随着伤害，手术，每日隐形眼镜磨损和年龄而增加。对抗菌蛋白和肽的研究对于阐明角膜和基于这些疗法的天然保护机制至关重要。我们的建议集中于四种抗菌蛋白的哺乳动物肽聚糖识别蛋白（PGLYRP）家族，这些蛋白存在于各种粘膜壁垒中，并在十年前确定。我们在人和小鼠角膜中发现了pGlyRP1，然后在人和小鼠角膜中找到了pGlyrp2，-3和-4。哺乳动物pGlyRP成员的功能通常没有被逐渐解散，尤其是在眼中鲜为人知的功能。昆虫中大的PGLYRP家族已知更多：它们主要是杀菌性的，有些水解肽聚糖（PGN）以限制炎症，而其他人则信号以托管和IMD途径诱导先天免疫和抗菌肽（AMP）诱导基因。哺乳动物PGLYRP1，-3和-4是针对革兰氏阳性和阴性细菌的杀菌性，PGLYRP2是amidase。在体外，它们与AMPS协同工作，体内协同作用是不知道的，但可疑。哺乳动物PGLYRP是否还调节先天免疫信号尚待全面研究。我们在R21提案中的中心假设是，哺乳动物角膜中的PGlyRP在阻止致病性细菌感染的同时，在促进先天免疫信号以用于角膜愈合和稳态方面。两个目标将检验该中心假设。1）在假单胞菌中测试PGLYRP1-4无效小鼠的抗菌防御能力（​​P）。 2A）测试PGLYRPS是否与角膜中的先天免疫信号（TLR2、4和NOD2）进行交流，以提高细胞因子和B-防御素，以及2B）是否通过促进上皮迁移来加快角膜愈合。对PGLYRP家族的这项探索性研究将对其在角膜中的作用以及对每个成员在促进角膜健康，遏制感染和开发靶向疗法的详细研究的基础上进行必要的评估。将来，我们的研究可能会导致预防或治疗方法，这些方法在手术前/后，在角膜上皮的角膜上皮，感染和储存移植角膜的储存之前调整了PGLYRP水平。 公共卫生相关性：我们对这种肽聚糖识别蛋白家族的发现将阐明角膜中的天然抗菌防御机制，治疗/预防性策略，用于调节其在角膜感染中的水平和功能，以及损伤或手术或手术相关的创伤，移植角膜或接触透镜储存。