Effects of autoantibodies on synaptic transmission in the retina

描述(申请人提供)：黑色素瘤相关性视网膜病变(MAR)是一种与皮肤恶性黑色素瘤相关的副肿瘤性视觉综合征，患者通常会经历夜间视力和闪光感觉的突然下降。MAR患者的视网膜电信号(ERG)记录以“负”波形为特征，其中由光感受器转导产生的a波正常，但主要由双极细胞激活产生的b波缺失或减少。值得注意的是，血清 来自MAR患者的已被证明标记视网膜双极细胞。这项拟议的研究测试了一种假设，即MAR患者血清中的自身抗体是针对转移的恶性黑素细胞中表达的蛋白质产生的，但随后针对的是双极细胞中具有功能的蛋白质复合体。本研究的目的是确定MAR中的视网膜抗原，阐明这些蛋白在正常双极细胞生理中的作用，并确定这些功能在MAR中是如何受到干扰的。这些目标将通过结合免疫组织化学、细胞生物学、生物化学和电生理学的多学科方法来解决。这些结果将对视觉的基本细胞过程产生新的见解，并将有助于我们理解癌症和自身免疫性视网膜病变之间的联系。

DESCRIPTION (provided by applicant): Melanoma Associated Retinopathy (MAR) is a paraneoplastic visual syndrome associated with cutaneous malignant melanoma in which patients typically experience a sudden decrease in night vision and sensations of shimmering lights. Electroretinogram (ERG) recordings from MAR patients are characterized by a "negative" waveform in which the a-wave, arising from photoreceptor transduction, is normal, but the b-wave, arising primarily from ON-bipolar cell activation, is absent or reduced. Significantly, serum from MAR patients has been shown to label retinal bipolar cells. The proposed research tests the hypothesis that autoantibodies in MAR patient serum are generated against proteins expressed in metastatic malignant melanocytes, but then target a protein complex functional in bipolar cells. The aims of the research are to identify the retinal antigens in MAR, to elucidate the role of these proteins in normal bipolar cell physiology, and determine how these functions are perturbed in MAR. The aims will be addressed with a multidisciplinary approach combining immunohistochemistry, cell biology, biochemistry, and electrophysiology. The results will generate new insights into cellular processes fundamental to vision and will contribute to our understanding of the link between cancer and autoimmune retinopathy.