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、屈光、保护性粘膜屏障。角膜感染对健康视力构成严重威胁。感染的风险随着受伤、手术、日常隐形眼镜佩戴和年龄的增长而增加。抗菌蛋白和肽的研究对于阐明角膜的自然保护机制和基于这些机制的治疗至关重要。我们的提案重点关注哺乳动物肽聚糖识别蛋白（PGLYRP）家族的四种抗菌蛋白，它们存在于各种粘膜屏障中，并在十多年前被发现。我们在人和小鼠的角膜中发现了PGLYRP1，随后又发现了PGLYRP2， -3和-4。哺乳动物PGLYRP成员的功能通常未被充分探索，特别是对它们在眼睛中的作用知之甚少。关于昆虫中的PGLYRP家族，我们知道的更多：它们大多具有杀菌作用，一些水解肽聚糖（PGN）以限制炎症，而另一些则向宿主发出信号，诱导先天免疫和抗菌肽（AMP）的基因。哺乳动物PGLYRP1， - 3和-4对革兰氏阳性和阴性细菌具有杀菌作用，PGLYRP2是一种酰胺酶。在体外，它们与AMPs协同作用，体内的协同作用尚不清楚，但怀疑。哺乳动物PGLYRPs是否也调节先天免疫信号还有待进一步研究。因此，哺乳动物pglyrp可能代表了一类新的角膜抗微生物免疫调节剂。在这项R21提案中，我们的中心假设是，哺乳动物角膜中的pglyrp可能具有双重作用，即阻止致病性细菌感染，同时促进角膜愈合和稳态的先天免疫信号。两个目标将检验这一中心假设。1)在铜绿假单胞菌角膜炎模型中检测Pglyrp1-4缺失小鼠的抗菌防御能力。2a)检测PGLYRPs是否与角膜内先天免疫信号（TLR2、4和Nod2）相互作用，上调细胞因子和b-防御素；2b) PGLYRPs是否通过促进上皮细胞迁移来促进角膜愈合。这项对PGLYRP家族的探索性研究将为其在角膜中的作用提供必要的评估，并为未来对每个成员在促进角膜健康、抑制感染和开发靶向治疗方面的详细研究奠定基础。在未来，我们的研究可能会导致在手术前后、移植角膜感染和储存时调整角膜上皮中PGLYRP水平的预防或治疗方法。