Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma

白细胞介素 6 和青光眼视网膜神经节细胞变性

• 批准号: 7863849
• 负责人: REBECCA M SAPPINGTON
• 金额: $ 34.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863849
• 关键词: Acute; Affect; Age; Antibodies; Antibody Therapy; Apoptotic; Axon; Axonal Transport; Blindness; Blocking Antibodies; Caliber; Cell Count; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Complex; DBA/2 Mouse; Data; Degenerative Disorder; Disease; Disease Progression; Effectiveness; Enzyme-Linked Immunosorbent Assay; Exposure to; Eye; Fluorescent in Situ Hybridization; Glaucoma; Immune; Immunohistochemistry; In Vitro; Inflammatory; Injection of therapeutic agent; Integration Host Factors; Interleukin-6; Knockout Mice; Magnetic Resonance Imaging; Manganese; Maps; Measures; Mediating; Messenger RNA; Microglia; Microspheres; Modeling; Mus; Neuroglia; Neurons; Ocular Hypertension; Optic Disk; Optic Nerve; Pathogenesis; Pathology; Pathway interactions; Pattern; Photoreceptors; Physiologic Intraocular Pressure; Physiological; Production; Proteins; Publishing; Recombinant Interleukins; Retina; Retinal; Retinal Detachment; Retinal Ganglion Cells; Risk Factors; Role; Series; Severity of illness; Signal Transduction; Source; Spatial Distribution; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; TimeLine; Tracer; Transcript; Vascular Permeabilities; Western Blotting; age related; anterior chamber; aqueous; axonal degeneration; cell type; cytokine; density; extracellular; gain of function; in vivo; insight; loss of function; mRNA Expression; mouse model; neuronal cell body; novel; overexpression; pressure; public health relevance; receptor; receptor expression; response; retrograde transport; superior colliculus Corpora quadrigemina; therapeutic target; uptake

DESCRIPTION (provided by applicant): Glaucoma is an age-related disease that blinds through the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. By 2020, 80 million people will suffer from the disease, making it the leading cause of irreversible blindness. While age is the leading risk factor, elevated intraocular pressure (IOP) remains the primary treatable factor. Elevated IOP challenges RGC survival directly, but also indirectly by affecting signals from other other cell types. Interleukin-6 is an inflammatory cytokine released by glial cells that we have shown can be neuroprotective for isolated RGCs under pressure (Sappington et al., 2006). However, the effectiveness of IL-6 as a potential therapeutic intervention for glaucoma is likely to depend upon age, IOP and the physiological state of the RGC. The purpose of this proposal is to determine the impact and therapeutic relevance of IL-6 for RGCs challenged by age and elevated IOP in vivo. Using two mouse models of glaucoma, we will determine whether glial cells are a primary source of IL-6 and how production of IL-6 relates to 1) receptivity of RGCs to IL-6 and 2) function and survival of RGCs. To determine directly the influence of the IL-6 pathway on RGC survival, we will manipulate expression or activity of IL-6 and its receptor IL-6R in both models. We will utilize the DBA/2 mouse, a chronic model of ocular hypertension, and an acute model we have developed that uses microbeads to occlude aqueous flow and elevate IOP. As a function of age and IOP in these models, we will quantify cell type-specific expression and localization of IL-6 and IL-6R. We will correlate these data with the decline of RGC function and progression of degeneration. For assessment of RGC degeneration, we will use morphometric techniques to quantify changes in RGC soma density in retina and changes in axon caliber and density in the optic nerve. To assess RGC function, we will quantify anterograde and retrograde axonal transport using active-uptake tracers and ionic activity using and manganese-enhanced magnetic resonance imaging. Data regarding IL-6 signaling and RGC pathology will serve to identify a therapeutic window(s) for manipulation of the IL-6 system in each model using loss and gain of function studies. For loss of function studies, we will utilize a commercially-available IL-6 knockout mouse and antibody therapy directed at neutralization of IL-6. For gain of function studies, we will utilize a commercially-available IL-6 overexpression mouse, recombinant IL-6 therapy and antibody therapy directed at activation of IL-6R. Completion of these aims will provide insight into many key components of IL-6 signaling in glaucoma: 1) the levels and pattern of IL-6 expression: 2) cell type-specific expression of IL-6 and IL6-R, and 3) how IL-6 signaling influences RGC survival and function during disease progression. PUBLIC HEALTH RELEVANCE: Glaucoma is the leading cause of irreversible blindness worldwide, involving the death of retinal ganglion cells (RGCs) and an association with elevated IOP. Elevated IOP challenges RGC survival directly, but also indirectly by affecting signals from other cells that could serve a protective role. We propose a series of studies to examine the potential of the inflammatory cytokine interleukin-6 as a therapeutic target to rescue RGCs in glaucoma.

描述（由申请人提供）：青光眼是一种年龄相关性疾病，通过视神经中视网膜神经节细胞（RGC）及其轴突的变性而致盲。到2020年，将有8000万人患有这种疾病，使其成为不可逆转的失明的主要原因。虽然年龄是主要的风险因素，但眼内压（IOP）升高仍然是主要的可治疗因素。升高的IOP直接挑战RGC存活，但也通过影响来自其他细胞类型的信号间接挑战RGC存活。白细胞介素-6是由神经胶质细胞释放的炎性细胞因子，我们已经证明其可以在压力下对分离的RGC具有神经保护作用（Sappington等人，2006年）。然而，IL-6作为青光眼的潜在治疗干预的有效性可能取决于年龄、IOP和RGC的生理状态。本提案的目的是确定IL-6对受年龄和体内IOP升高挑战的RGC的影响和治疗相关性。使用两种青光眼小鼠模型，我们将确定神经胶质细胞是否是IL-6的主要来源，以及IL-6的产生如何与1）RGC对IL-6的感受性和2）RGC的功能和存活相关。为了直接确定IL-6通路对RGC存活的影响，我们将在两种模型中操纵IL-6及其受体IL-6 R的表达或活性。我们将利用DBA/2小鼠，一种慢性高眼压模型，以及我们开发的一种急性模型，该模型使用微珠阻塞房水流并升高IOP。在这些模型中，作为年龄和IOP的函数，我们将定量IL-6和IL-6 R的细胞类型特异性表达和定位。我们将这些数据与RGC功能的下降和变性的进展相关联。为了评估RGC变性，我们将使用形态测量技术来量化视网膜中RGC索马密度的变化以及视神经中轴突口径和密度的变化。为了评估RGC功能，我们将使用主动摄取示踪剂和离子活性以及锰增强磁共振成像来量化顺行和逆行轴突运输。关于IL-6信号传导和RGC病理学的数据将用于使用功能丧失和获得研究来鉴定用于在每个模型中操纵IL-6系统的治疗窗口。对于功能丧失研究，我们将利用市售IL-6敲除小鼠和针对中和IL-6的抗体疗法。为了获得功能研究，我们将利用市售IL-6过表达小鼠、重组IL-6疗法和针对IL-6 R活化的抗体疗法。这些目标的完成将提供对青光眼中IL-6信号传导的许多关键组分的深入了解：1）IL-6表达的水平和模式; 2）IL-6和IL 6-R的细胞类型特异性表达;以及3）IL-6信号传导如何影响疾病进展期间RGC的存活和功能。 公共卫生关系：青光眼是世界范围内不可逆失明的主要原因，涉及视网膜神经节细胞（RGC）的死亡以及与IOP升高的相关性。升高的IOP直接挑战RGC的存活，但也通过影响来自其他细胞的信号间接挑战RGC的存活，这些信号可以起到保护作用。我们提出了一系列的研究，以检查潜在的炎症细胞因子白细胞介素-6作为一个治疗目标，以挽救视网膜节细胞在青光眼。