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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.

摘要阿尔法疱疹病毒是普遍存在的病毒的一个亚家族，可以引起一系列临床显著的包括急性视网膜坏死(ARN)致盲在内的疾病。不幸的是，即使有及时的抗病毒药物治疗后，视网膜内会发生不可逆转的病变，并显著增加视力风险- 可能会出现并发症，进一步危及本已很差的视力预后。自从……出现以来阿昔洛韦，在治疗具有临床意义的疱疹感染方面没有重大进展，尽管视力下降的并发症，对病毒的免疫反应知之甚少在视网膜内。这一提议将提供对先天免疫反应的基本理解。视网膜内的HSV-1病毒，同时培养职业发展中的关键技能。这样做的长期目标是该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治疗方法，以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。这项K08提案的科学目标是测试I型干扰素(IFN)是宿主对视网膜病毒感染和视网膜小胶质细胞内Toll样受体-3激活的中枢防御这种先天免疫反应。我们建议评估对疱疹病毒感染的先天免疫反应。通过利用几种免疫基因敲除的小鼠系、人视网膜细胞培养物和玻璃体从ARN患者的样本中评估IFN的作用及其在神经炎症中的作用。三我们将利用聚焦的特定目标来检验我们的假设：1)确定负责视网膜内的HSV先天免疫；2)确定下游IFN在宿主防御病毒中的作用视网膜感染；3)确定急性视网膜坏死的主要干扰素亚型和细胞来源从人体样本中提取。职业发展的目标是发展成为一名多产且独立的临床医生兼科学家。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级的教师队伍在神经免疫学、病毒感染和先天免疫信号方面的专业知识将作为指导团队。机构资源、指导团队和职业发展计划已开发为特别是促进视网膜神经炎症研究的科学独立性。