Corneal neuropeptides and herpetic stromal keratitis

角膜神经肽与疱疹性基质角膜炎

• 批准号: 8912631
• 负责人: Susmit Suvas
• 金额: $ 15.64万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912631
• 关键词: Address; Affect; Afferent Neurons; Agonist; Alcohol or Other Drugs use; Antibodies; Apoptosis; Biological Assay; Blindness; C57BL/6 Mouse; Capsaicin; Cells; Chronic; Clinical; Cornea; Corneal Injury; Dendritic Cells; Detection; Development; Dichloromethylene Diphosphonate; Epidermal Growth Factor; Goals; Health; Herpesvirus 1; Herpetic Keratitis; Immune; In Situ Nick-End Labeling; Infection; Inflammation; Inflammatory; Interleukin-12; Keratitis; Knowledge; Learning; Lesion; Liposomes; Measures; Mediating; Migration Assay; Mus; Natural Killer Cells; Nerve; Nerve Fibers; Nerve Growth Factors; Neuropeptides; Pathogenesis; Peptides; Pharmacologic Substance; Property; Reporting; Research; Role; Severities; Staining method; Stains; Substance P; TACR1 gene; Testing; Time; Topical application; Viral; Viral Load result; Virus; Work; Wound Healing; base; cell type; cytokine; cytotoxicity; in vivo; innate immune function; macrophage; migration; monocyte; mouse model; novel; novel strategies; pre-clinical; receptor; research study; response; tissue repair

DESCRIPTION (provided by applicant): Corneal infection with herpes simplex virus-1 (HSV-1) causes herpetic stromal keratitis (HSK), a leading cause of infection-induced corneal blindness worldwide. Despite intensive research and substantial progress in understanding the pathogenesis of HSK, the management of this condition continues to be challenging. One significant hurdle is our poor understanding of the role of neuropeptides, secreted by abundant corneal nerve fibers, in the development of HSK lesions. Lack of such knowledge is an important problem because neuropeptides are well known to regulate both inflammation and tissue repair. The objective of this application is to determine what regulates substance P (SP) neuropeptide levels in the cornea after ocular HSV-1 infection, and how SP interactions with its receptor NK1R control the viral load and affects the development of HSK lesions. We will approach these questions in a mouse model by using SP-/- and NK1R-/- mice. We recently reported that blocking SP-NK1R interactions in the absence of replicating virus (clinical period) significantly reduced the development of HSK lesions. However, lack of SP-NK1R interactions during active viral replication in the cornea (pre-clinical period), enhances the severity of HSK lesions, as noted in SP- /- and NK1R-/- mice. Our preliminary results showed delayed viral clearance and reduced levels of epidermal growth factor (EGF), a corneal wound healing factor, in NK1R-/- mice. On the basis of our preliminary results, we hypothesize that SP, produced in HSV-1 infected corneas by macrophages and corneal nerves, promotes corneal tissue repair and regulates the influx, survival, and function of innate immune cells involved in viral clearance therefore, enhancing SP-mediated effects during active viral replication should reduce the development of severe HSK lesions. Three aims are proposed to address our hypothesis. In aim 1, experiments will be carried out to determine the role of corneal macrophages and sensory neurons in regulating the levels of SP peptide in HSV-1 infected corneas during the pre-clinical and clinical periods of HSK, respectively. In aim 2, experiments will be carried out t determine whether SP-NK1R interactions regulate viral load in the cornea by promoting the migration, survival, and functions of dendritic cells (DCs), inflammatory monocytes (IM) and natural killer (NK) cells in HSV-1 infected cornea. In aim 3, we will determine whether enhancing SP-mediated effects during the active viral replication period through topical application of EGF alone, or in combination with subconjunctival administration of SP, modulates the development of severe HSK lesions. The information generated by this study could aid in the development of novel pharmaceutical strategies to reduce HSV-1 induced chronic inflammation by promoting viral clearance and corneal tissue repair.

描述（由申请人提供）：用单纯疱疹病毒1（HSV-1）引起疱疹性基质角膜炎（HSK），这是全球感染引起的角膜失明的主要原因。尽管在理解HSK的发病机理方面进行了深入的研究和实质性进展，但这种情况的管理仍然具有挑战性。一个重大的障碍是我们对由大量角膜神经纤维分泌的神经肽的作用的不良理解，在HSK病变的发展中。缺乏这种知识是一个重要的问题，因为众所周知，神经肽可以调节炎症和组织修复。该应用的目的是确定是什么调节眼部HSV-1感染后角膜中P（SP）神经肽水平的调节，以及SP与其受体NK1R的相互作用如何控制病毒载量并影响HSK病变的发展。我们将使用SP - / - 和NK1R - / - 小鼠在鼠标模型中解决这些问题。我们最近报道说，在没有复制病毒（临床时期）的情况下阻断SP-NK1R相互作用会大大降低HSK病变的发展。然而，如SP- / - / - 和NK1R - / - 小鼠所指出的那样，在角膜（临床前）中缺乏SP-NK1R相互作用（临床前）（临床前时期），会增强HSK病变的严重程度。我们的初步结果显示，病毒清除率延迟，表皮生长因子水平降低（EGF），这是NK1R - / - 小鼠中的角膜伤口愈合因子。 On the basis of our preliminary results, we hypothesize that SP, produced in HSV-1 infected corneas by macrophages and corneal nerves, promotes corneal tissue repair and regulates the influx, survival, and function of innate immune cells involved in viral clearance therefore, enhancing SP-mediated effects during active viral replication should reduce the development of severe HSK lesions.提出了三个目的来解决我们的假设。在AIM 1中，将进行实验，以确定角膜巨噬细胞和感觉神经元在HSK的临床前和临床期间分别在HSV-1感染角膜中调节SP肽水平。在AIM 2中，将进行实验t t确定SP-NK1R相互作用是否通过促进树突状细胞（DC）的迁移，生存和功能（DC），炎症单核细胞（IM）和天然杀伤（NK）细胞（NK）细胞来调节角膜中的病毒载量。在AIM 3中，我们将确定通过单独使用EGF的局部应用或与SP的下施用相结合，可以增强SP介导的效果，从而调节严重的HSK病变的发展。这项研究产生的信息可以帮助发展新型药物策略，以减少HSV-1通过促进病毒清除和角膜组织修复来诱导慢性炎症。