VIP and Disease Resolution of Bacterial-Induced Ocular Infection

VIP 和细菌引起的眼部感染的疾病解决

基本信息

批准号：
9024544
负责人：
Elizabeth Berger
金额：
$ 38.05万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9024544
关键词：
Adverse effects Affect Aftercare Aliquot Amino Acids Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotic Resistance Antibiotic Therapy Antibiotics Automobile Driving Bacterial Infections Biological Models Biological Preservation Blindness CD59 Antigen Cells Clinical Data Communicable Diseases Contact Lenses Cornea Corneal Injury Development Disease Disease Outcome Drug Delivery Systems Economics Equilibrium Eye Eye Infections Goals Health Homeostasis Human Immune Immune response Immune system Immunomodulators Impairment Inbred BALB C Mice Incidence Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-17 Keratitis Laboratories Light Lipoxins Modality Mus Natural Immunity Nerve Nervous system structure Neuropeptides Neurosecretory Systems Organism Pathogenesis Perforation Play Production Pseudomonas aeruginosa Regulation Research Design Resistance Resolution Role Solid Steroids Surface T-Lymphocyte Techniques Testing Therapeutic Tissues Topical application Treatment Cost United States Vasoactive Intestinal Peptide Vision Visual Visual Acuity Visual system structure base clinical application clinically relevant cytotoxic human disease lipid mediator microbial mouse model novel novel therapeutic intervention novel therapeutics pathogen pre-clinical preclinical study release factor response restoration

项目摘要

DESCRIPTION (provided by applicant): Background. Pseudomonas aeruginosa (PA)-induced keratitis is one of the most common and destructive of bacterial diseases, ultimately culminating in blindness. This opportunistic, Gram-negative organism is best known to cause bacterial keratitis in extended contact lens wearers. In the United States alone the incidence of microbial keratitis is 25,000-30,000 cases annually with cost of treatment estimated at $15-30 million. Objective/Hypothesis. This sight-threatening disease is in large part a consequence of the inflammatory response invoked by the host, which depends on the regulation of immune cells, balance between pro- and anti-inflammatory factors released by these cells and the microenvironment, and effective restoration of tissue homeostasis. In this regard and in light of increasing incidence of antibiotic resistance, vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, has been implicated as a potent endogenous immunomodulator that affects the immune response in an anti-inflammatory manner. The goal is to delineate the VIP-induced pro-resolving mechanisms of inflammation and innate immunity using a murine model of corneal infectious disease. Furthermore, initiate pre-clinical studies for VIP as a therapeutic treatment for corneal infectious disease. Specific Aims. This proposal intends to: 1) ascertain the effects of VIP regarding expression/activation of specialized pro-resolving mediators (SPMs) of inflammation; 2) examine how VIP influences γδ T cells and the production of IL-17 in driving inflammatory resolution; and 3) establish the efficacy of VIP treatment as a clinically relevant therapy for bacterial keratitis against multiple strains of PA. Study Design. Ocular infection will be induced as follows: the right eye of each animal will be scarified, and a 5 mL aliquot containing 1 x 106 CFU PA will be topically applied to the wounded corneal surface. Disease response and mechanisms of resolution will be compared between experimental (VIP-treated B6 mice) and control (PBS-treated B6 mice and PBS-treated BALB/c mice) animals using a number of well-established techniques to assess the activation state of immune cells, expression and activation of lipid mediators (lipoxins, resolvins, protectins), and other parameters of inflammation. In addition, studies will be carried out to establish pre-clinically relevant treatment modalities for VIP (e.g., modes of drug delivery, initiation of treatment post-infection, efficacy against cytotoxic and invasive strains of PA). Impact. The project examines therapeutically how interactions between the immune and neuroendocrine systems play an essential role in the resolution of ocular infection and subsequent preservation of the visual nervous system and visual acuity. In particular, the proposed studies will establish a solid basis of pre-clinical relevance to human treatment of bacterial keratitis.

描述（由申请人提供）：背景：铜绿假单胞菌 (PA) 引起的角膜炎是最常见和最具破坏性的细菌性疾病之一，最终导致失明。众所周知，这种机会性革兰氏阴性微生物会长期引起细菌性角膜炎。仅在美国，每年就有 25,000-30,000 例隐形眼镜佩戴者罹患微生物性角膜炎，并需要支付治疗费用。估计价值 15-3000 万美元。目标/假设这种威胁视力的疾病很大程度上是宿主引起的炎症反应的结果，这取决于免疫细胞的调节、促炎因子和抗炎因子之间的平衡。血管活性肠肽（VIP），一种 28 个氨基酸，可以通过这些细胞和微环境发挥作用，并有效恢复组织稳态。神经肽被认为是一种有效的内源性免疫调节剂，以抗炎方式影响免疫反应，目的是利用角膜感染性疾病的小鼠模型来描述 VIP 诱导的炎症和先天免疫的缓解机制。启动 VIP 作为角膜感染性疾病治疗的临床前研究。具体目标是： 1) 确定 VIP 对特殊促消退介质表达/激活的影响。 (SPM) 炎症；2) 检查 VIP 如何影响 γδ T 细胞和 IL-17 的产生以促进炎症消退；3) 确定 VIP 治疗作为针对多种 PA 菌株的细菌性角膜炎的临床相关疗法的疗效。研究设计。如下诱导：将每只动物的右眼划伤，将含有 1 x 106 CFU PA 的 5 mL 等分试样局部涂抹到受伤的角膜表面，将比较实验（VIP-）之间的疾病反应和消退机制。使用许多成熟的技术来评估免疫细胞的激活状态、脂质介质的表达和激活此外，还将开展研究以确定 VIP 的临床前相关治疗方式（例如，药物输送方式、感染后开始治疗、对抗细胞毒性影响的功效）。这些项目在治疗上研究了免疫系统和神经内分泌系统之间的相互作用如何在解决眼部感染以及随后保护视觉神经系统和视力方面发挥重要作用。特别是，拟议的研究将为人类治疗细菌性角膜炎的临床前相关性奠定坚实的基础。