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Innate Immunity to Viral Infection of the Retina

视网膜对病毒感染的先天免疫

基本信息

批准号：
10641586
负责人：
Christopher Dale Conrady
金额：
$ 23.47万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641586
关键词：
Acute Disease Acute Retinal Necrosis Syndrome Acyclovir Automobile Driving Biopsy Blindness Brain Cell Culture Techniques Cells Central Nervous System Infections Cessation of life Chimera organism Chronic Disease Clinical Treatment Cornea Data Development Development Plans Disease Faculty Family Functional disorder Future Goals Herpesviridae Herpesviridae Infections Herpesvirus 1 Histopathology Host Defense Human IFNAR1 gene Image Immune Immune response Immune signaling Immunity Infection Inflammation Inflammatory Innate Immune Response Institution Interferon Type I Interferons Investigation Knockout Mice Leucocytic infiltrate Medical center Meningoencephalitis Mentors Mentorship Microglia Molecular Mus Natural Immunity Nebraska Necrosis Induction Neurocognitive Ophthalmology Outcome Pathologic Pathology Pathway interactions Patients Primary Infection Production Productivity Prognosis Quality of life Research Research Personnel Resources Retina Retinal Detachment Retinal Diseases Retinitis Risk Role Sampling Scientist Signal Transduction Simplexvirus Source Specimen TLR3 gene Testing Therapeutic Tissues Toll-like receptors Universities Viral Virus Virus Activation Virus Diseases Virus Replication Vision Visual Visual impairment Wild Type Mouse career development cell type chemokine clinically significant cytokine fundus imaging glial activation human tissue improved in vivo insight laboratory facility mouse model neuroimmunology neuroinflammation novel novel therapeutics preservation programs response retinal damage sensor skills type I interferon receptor vaginal mucosa vision science

项目摘要

SUMMARY Alpha herpesviruses are a subfamily of ubiquitous viruses that can cause a spectrum of clinically-significant diseases including blindness from acute retinal necrosis (ARN). Unfortunately, even with timely antiviral treatment, irreversible pathological changes occur within the retina and significantly increase the risk of vision- threatening complications to further compromise an already poor visual prognosis. Since the advent of acyclovir, there have been no major advances in the treatment of clinically-significant herpes infections despite the vision-degrading complications and very little is known in regards to the immune response to the virus within the retina. This proposal will provide a fundamental understanding of the innate immune response to HSV-1 within the retina, while developing critical skills in career development. The long-term goal of this project is to acquire the scientific skills needed to enhance our understanding and pursue novel therapies to preserve vision and reduce complications related to ARN as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that type I interferons (IFNs) are central to host defense to viral infection of the retina and that toll-like receptor-3 within retinal microglia activate this innate immune response. We propose evaluating the innate immune response to herpes virus infections of the retina by utilizing several immune knock-out mouse lines, human retinal cell cultures, and vitreous specimens from patients with ARN to assess the role of IFNs and their role in neuroinflammation. Three focused specific aims will be utilized to test our hypothesis: 1) Identify pathways and cell types responsible for HSV innate immunity within the retina; 2) Determine the role of downstream IFNs in host defense against viral infection of the retina; 3) Identify the predominate IFN subtype and cellular source in acute retinal necrosis from human samples. The career development objective is to develop the mentorship and expertise needed to become a productive and independent clinician-scientist. The Department of Ophthalmology and Visual Sciences and the University of Nebraska Medical Center have state-of-the-art laboratory facilities and world-class faculty with expertise in neuroimmunology, viral infections, and innate immune signaling to serve as the mentoring team. The institutional resources, mentorship team, and career development plan have been developed to specifically promote scientific independence in the study of neuroinflammation of the retina.

总结 α疱疹病毒是普遍存在的病毒的一个亚家族，其可引起一系列临床显著的包括急性视网膜坏死（ARN）导致的失明在内的疾病。不幸的是，即使有及时的抗病毒治疗后，视网膜内发生不可逆的病理变化，并显着增加视力的风险- 有可能出现并发症，进一步损害已经很差的视力预后。问世以来无环鸟苷，在治疗临床上显著的疱疹感染方面没有重大进展，尽管视力下降的并发症，以及对病毒的免疫反应知之甚少在视网膜内。这项提案将提供一个基本的理解先天免疫反应， HSV-1在视网膜内，同时发展职业发展的关键技能。长期目标是项目是获得所需的科学技能，以提高我们的理解和追求新的疗法，作为一名独立的临床科学家，保护视力并减少与ARN相关的并发症。该K 08提案的科学目的是检验I型干扰素（IFN）是视网膜病毒感染的宿主防御中枢和视网膜小胶质细胞内的Toll样受体-3激活这种先天免疫反应。我们建议评估先天免疫反应疱疹病毒感染通过利用几种免疫敲除小鼠系、人视网膜细胞培养物和玻璃体从ARN患者的标本，以评估干扰素的作用和它们在神经炎症中的作用。三将利用集中的具体目标来测试我们的假设：1）确定负责视网膜内的HSV先天免疫; 2）确定下游IFN在宿主防御病毒感染中的作用。 3）确定急性视网膜坏死的主要干扰素亚型和细胞来源人类样本。职业发展的目标是发展成为一个富有成效和独立的临床科学家。眼科和视觉科学系，内布拉斯加大学医学中心拥有最先进的实验室设施和世界一流的教师队伍，神经免疫学、病毒感染和先天免疫信号传导方面的专业知识，担任指导团队。机构资源、指导团队和职业发展计划已经制定，特别是促进视网膜神经炎症研究的科学独立性。