Melanoma-associated retinopathy: detection and mechanisms

黑色素瘤相关视网膜病变：检测和机制

• 批准号: 10197934
• 负责人: ROBERT M DUVOISIN
• 金额: $ 37.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197934
• 关键词: Alternative Splicing; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Biological; Cations; Cells; Clinic; Cognitive; Contrast Sensitivity; Cutaneous; Cutaneous Melanoma; Detection; Development; Diagnostic; Diagnostic tests; Disease; Down-Regulation; Electroretinography; Epitopes; Esthesia; Exons; Eye; Foundations; Goals; Immune checkpoint inhibitor; Immunotherapy; Incidence; Introns; Length; Light; Link; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Messenger RNA; MicroRNAs; N-terminal; Neoplasm Metastasis; Neurologic; Neurons; Night Blindness; Paraneoplastic Syndromes; Patient risk; Patients; Photophobia; Prevalence; RNA Splicing; Reporting; Research; Retina; Retinal Diseases; Risk; Serum; Specimen; Symptoms; Syndrome; TRPM1 gene; Testing; Translations; Treatment Protocols; Tumor Suppressor Proteins; Variant; Vision; Visual; base; cancer cell; clinical Diagnosis; cohort; experience; immunogenic; immunoreactivity; insight; melanocyte; melanoma; novel; novel diagnostics; polypeptide; prognostic; prognostic assays; response; targeted treatment; transcriptome sequencing; tumor

Project Summary Some cutaneous malignant melanoma (CMM) patients experience a sudden and rapid decline in their night vision often accompanied by photophobia and a sensation of shimmering light. These symptoms are a hallmark of a paraneoplastic autoimmune syndrome known as melanoma-associated retinopathy (MAR), which is clinically diagnosed by a reduced b-wave on the electroretinogram. We and others have identified the TRPM1 cation channel as the autoantigen. TRPM1 channels are expressed in melanocytes and retinal ON- bipolar cells, thus autoantibodies against TRPM1 block ON bipolar cell responses. A tumor suppressor microRNA, miR-211, is encoded within the 6th intron of TRPM1 and co-transcribed with TRPM1. Full-length TRPM1 and miR-211 are down regulated in metastatic disease, yet this is when TRPM1 autoantibodies are typically detected. We propose that the autoantibodies are generated against truncated, antigenic TRPM1 polypeptides encoded by abnormal TRPM1 mRNA splice variants, associated with reduced expression of miR-211.. The overall rationale of the proposed studies is that the occurrence of TRPM1 autoantibodies is more widespread in CMM patients than suggested by the incidence of clinically diagnosed MAR, and that the increased use of targeted and immuno therapies may heighten the risk of MAR. The proposed project aims to determine the incidence of TRPM1 autoantibodies and sub-clinical MAR among CMM patients and whether it varies according to treatment. Further, we aim to identify which TRPM1 mRNA splice variants give rise to immunoreactive TRPM1 polypeptides and test our hypothesis that these polypeptides are present in CMM specimens from patients with TRPM1 autoantibodies and sub-clinical MAR, and are associated with a down- regulation of miR-211. Thus, we will generate new insights into the cellular mechanisms underlying MAR, which may be further relevant to paraneoplastic autoimmune diseases in general. Potential applications of this research include the development of a prognostic/diagnostic test that can be used in the clinic for assessing CMM patients' risk of MAR and tumor metastasis.

项目概要 一些皮肤恶性黑色素瘤 (CMM) 患者的夜间睡眠质量突然迅速下降 视力通常伴有畏光和闪烁光的感觉。这些症状是 副肿瘤性自身免疫综合征的标志，称为黑色素瘤相关视网膜病 (MAR)， 临床上可通过视网膜电图上的 b 波减少来诊断。我们和其他人已经确定了 TRPM1阳离子通道作为自身抗原。 TRPM1 通道在黑素细胞和视网膜 ON- 中表达 双极细胞，因此针对 TRPM1 的自身抗体会阻断双极细胞的反应。肿瘤抑制剂 microRNA（miR-211）在 TRPM1 的第 6 个内含子内编码，并与 TRPM1 共转录。全长 TRPM1 和 miR-211 在转移性疾病中下调，但此时 TRP​​M1 自身抗体 通常检测到。我们建议针对截短的抗原性 TRPM1 产生自身抗体 由异常 TRPM1 mRNA 剪接变体编码的多肽，与以下表达减少相关 miR-211.. 拟议研究的总体原理是 TRPM1 自身抗体的发生率更高 CMM 患者中的广泛性比临床诊断的 MAR 的发生率所暗示的要高，并且 增加使用靶向和免疫疗法可能会增加 MAR 的风险。拟议项目旨在 确定 CMM 患者中 TRPM1 自身抗体和亚临床 MAR 的发生率以及是否 根据治疗的不同而不同。此外，我们的目标是确定哪些 TRPM1 mRNA 剪接变体会产生 免疫反应性 TRPM1 多肽并检验我们的假设，即这些多肽存在于 CMM 中 来自具有 TRPM1 自身抗体和亚临床 MAR 的患者的标本，并且与下调相关 miR-211 的调节。 因此，我们将对 MAR 背后的细胞机制产生新的见解，这可能会进一步 一般与副肿瘤性自身免疫性疾病相关。这项研究的潜在应用包括 开发可在临床中用于评估 CMM 患者的风险的预后/诊断测试 MAR和肿瘤转移。