Mechanism of Retinal Damage in Autoimmune Retinopathy

描述(申请人提供)：视网膜变性是世界上导致视力丧失的主要原因之一。自身免疫性视网膜病变，包括副肿瘤性视网膜病变，如癌症相关的视网膜病变和黑色素瘤相关的视网膜病变，是由抗视网膜蛋白的自身抗体介导的进行性视觉损伤。自身免疫性视网膜病变目前是一种无法治疗的眼病，对其致病机理的了解仍不完全。 提出的假设是，自身抗体通过增加细胞内钙激活视网膜细胞的凋亡性死亡而导致视网膜病变。视网膜细胞的大量死亡会导致严重的组织损伤、视力丧失，最终导致失明。为了确定一般的治疗策略，需要对视网膜病变的常见机制进行评估，该机制与各种视网膜特异性自身抗体有关。 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准确的关键时间点，以便进行治疗干预以治疗临床症状。这项建议的目的是利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，并为血清阳性患者定义临床和电生理标记物(指示物)，以启动对这些患者的最佳医疗评估和护理。为了实现这些目标，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是否激活启动细胞凋亡的相同机制；(2)确定具有特定抗视网膜自身抗体的视网膜病患者的表型；(3)利用大鼠模型和视网膜电描记术确定自身抗体在改变视网膜细胞功能中的作用；(4)在抗体诱导的视网膜病变大鼠模型中，研究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.