Mechanism of Retinal Damage in Autoimmune Retinopathy

描述（由申请人提供）：视网膜变性是世界上视力丧失的主要原因之一。自身免疫性视网膜病，包括副肿瘤性视网膜病，如癌症相关性视网膜病和黑素瘤相关性视网膜病，是由针对视网膜蛋白的自身抗体介导的进行性视觉障碍。自身免疫性视网膜病变是目前无法治疗的眼病，对其致病性的了解仍然不完全。 所提出的假说是，自身抗体通过增加细胞内钙激活视网膜细胞凋亡而诱导视网膜病变。视网膜细胞的大量死亡会导致严重的组织损伤，视力丧失，最终失明。为了确定一般的治疗策略，需要评估与各种视网膜特异性自身抗体相关的视网膜病变的常见机制。 长期目标是确定自身免疫性视网膜病变中视网膜损伤的机制，并根据这些发现，确定治疗干预治疗临床症状的精确，关键时间点。本提案的目的是使用体内大鼠模型和体外方法建立患者抗视网膜抗体的致病特性，并定义血清阳性患者的临床和电生理标志物（指标），以便对这些患者进行最佳医学评估和护理。为实现这些目标，提出了以下具体目标：（1）确定不同抗视网膜特异性的自身抗体在体外启动凋亡中是否激活相同的机制，（2）确定具有特异性抗视网膜自身抗体的视网膜病变患者的表型，（3）使用大鼠模型和视网膜电图确定自身抗体在改变视网膜细胞功能中的作用，以及（4）在抗体诱导的视网膜病变大鼠模型中检查在治疗视网膜变性中阻止细胞凋亡的可能途径。

DESCRIPTION (provided by applicant): Retinal degeneration is one of the leading causes of visual loss in the world. Autoimmune retinopathies, including paraneoplastic retinopathies such as cancer-associated retinopathy and melanoma-associated retinopathy, are progressive visual impairments that are mediated by autoantibodies against retinal proteins. Autoimmune retinopathy is currently an untreatable eye disease, and an understanding of its pathogenicity is still incomplete. The proposed hypothesis is that autoantibodies induce retinopathy through the activation of apoptotic death in retinal cells by increasing intracellular calcium. A massive death of retinal cells leads to significant tissue damage, loss of vision, and finally, blindness. To determine general treatment strategies, assessment is needed of a common mechanism of retinopathy that is associated with autoantibodies of various retinal specificities. The long-term goal is to define the mechanism of retinal damage in autoimmune retinopathy and, based on these findings, to identify precise, critical time points for therapeutic intervention to treat clinical symptoms. The objectives of this proposal are to establish pathogenic properties of patients' anti-retinal antibodies using an in vivo rat model and in vitro methods, and to define clinical and electrophysiological markers (indicators) for seropositive patients in order to initiate optimum medical evaluation and care for these patients. To achieve these objectives, the following specific aims are proposed: (1) To determine whether autoantibodies of different anti-retinal specificities activate the same mechanism in initiating apoptosis in vitro, (2) To define the phenotype of retinopathy patients with specific anti-retinal autoantibodies, (3) To determine the role of autoantibodies in altering the function of retinal cells using the rat model and electroretinography, and (4) To examine possible pathways to stop apoptosis in treating retinal degeneration in the rat model of antibody-induced retinopathy.