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

• 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
• 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

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。这种机会性的革兰氏阴性菌最广为人知的是在佩戴隐形眼镜的人群中引起细菌性角膜炎。仅在美国，每年细菌性角膜炎的发病率为25,000-30,000例，治疗费用估计为1,500 - 3,000万美元。目的/假说。这种威胁视力的疾病在很大程度上是由宿主引起的炎症反应的结果，这取决于免疫细胞的调节，这些细胞和微环境释放的促炎因子和抗炎因子之间的平衡，以及组织稳态的有效恢复。在这方面，鉴于越来越多的抗生素耐药性的发生，血管活性肠肽（VIP），一个28个氨基酸