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: 10617761
• 负责人: ROBERT M DUVOISIN
• 金额: $ 38.5万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617761
• 关键词: Alternative Splicing; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Biological; Cations; Cells; Clinic; Contrast Sensitivity; Cross Reactions; Cutaneous; Cutaneous Melanoma; Detection; Development; Diagnostic; Diagnostic tests; Disease; Down-Regulation; Electroretinography; Epitopes; Esthesia; Exons; Eye; Foundations; Genetic Transcription; Goals; Immune checkpoint inhibitor; Immunotherapy; Impaired cognition; 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; 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.

项目摘要 一些皮肤恶性黑色素瘤（CMM）患者在夜间经历突然和快速下降， 经常伴随着恐惧症和闪烁的光的感觉的视觉。这些症状是 黑色素瘤相关性视网膜病变（MAR）是一种副肿瘤性自身免疫综合征的标志， 临床上通过视网膜电图上的b波降低来诊断。我们和其他人已经确定了 TRPM 1阳离子通道作为自身抗原。TRPM1通道在黑素细胞和视网膜ON-1中表达。 因此，针对TRPM 1的自身抗体阻断ON双极细胞应答。肿瘤抑制 microRNA（miR-211）编码于TRPM1的第6内含子内，与TRPM1共转录。全长 TRPM1和miR-211在转移性疾病中下调，但这是当TRPM1自身抗体在转移性疾病中表达时。 通常检测。我们提出，自身抗体是针对截短的抗原性TRPM 1产生的。 TRPM1 mRNA剪接变异体异常编码的多肽，与TRPM1 mRNA剪接变异体的表达减少相关。 miR-211.. 拟议研究的总体原理是TRPM 1自身抗体的发生率更高， 广泛存在于CMM患者中，而不是临床诊断的MAR发生率所提示的，并且 增加靶向和免疫疗法的使用可能会增加MAR的风险。拟议的项目旨在 确定CMM患者中TRPM1自身抗体和亚临床MAR的发生率， 因治疗而异。此外，我们的目标是确定哪些TRPM 1 mRNA剪接变异体引起 免疫反应性TRPM 1多肽，并测试我们的假设，这些多肽存在于CMM TRPM1自身抗体和亚临床MAR患者的标本，并与降低- 调节miR-211。 因此，我们将对MAR的细胞机制产生新的见解，这可能是进一步的研究。 与一般的副肿瘤性自身免疫性疾病有关。这项研究的潜在应用包括 开发一种预后/诊断测试，可用于临床评估CMM患者的风险， MAR和肿瘤转移。