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)患者夜间症状突然迅速下降。 视觉通常伴随着畏光和一种闪光的感觉。这些症状是 一种被称为黑色素瘤相关性视网膜病变(MAR)的副肿瘤性自身免疫综合征的标志 临床诊断为视网膜电信号b波降低。我们和其他人已经确定了 以TRPM1阳离子通道作为自身抗原。TRPM1通道在黑素细胞和视网膜上表达。 因此，针对TRPM1的自身抗体可阻断双极细胞的反应。一种肿瘤抑制因子 MicroRNA miR-211编码于TRPM1的第6内含子，并与TRPM1共转录。全长 TRPM1和miR-211在转移性疾病中表达下调，但这是TRPM1自身抗体 通常会检测到。我们认为自身抗体是针对截短的抗原性TRPM1产生的。 TRPM1基因异常剪接变异体编码的多肽与其低表达相关 MIR-211.. 拟议研究的总体理论基础是TRPM1自身抗体的发生率更高 在CMM患者中普遍存在，而不是由临床诊断的MAR的发生率所提示的，并且 更多地使用靶向和免疫疗法可能会增加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的发生率以及是否 根据治疗的不同而有所不同。此外，我们的目标是确定哪些TRPM1 mrna剪接变异体会引起 并验证我们的假设，即这些多肽存在于CMM中 来自TRPM1自身抗体和亚临床MAR患者的样本，并与Down-Down- MiR-211的调控。 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有关。这项研究的潜在应用包括 临床上可用于评估CMM患者发病风险的预后/诊断试验的发展 MAR与肿瘤转移的关系。