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.

项目摘要 一些皮肤恶性黑色素瘤（CMM）患者的夜晚突然迅速下降 视力通常伴随着恐惧症和闪闪发光的感觉。这些症状是 副肿瘤自身免疫性综合征的标志称为黑色素瘤相关的视网膜病（MAR） 在临床上通过电视图上的B波减少诊断。我们和其他人已经确定了 TRPM1阳离子通道作为自动抗原。 TRPM1通道在黑素细胞和视网膜上表达 双极细胞，因此在双极细胞反应上针对TRPM1块的自身抗体。肿瘤抑制剂 microRNA，miR-211在TRPM1的第6个内含子中编码，并与TRPM1共转录。全长 TRPM1和miR-211在转移性疾病中受到调节，但这是TRPM1自身抗体是 通常检测到。我们建议对截短的抗原TRPM1产生自身抗体 由异常TRPM1 mRNA剪接变体编码的多肽与降低的表达有关 mir-211 .. 拟议研究的总体原理是TRPM1自身抗体的发生更多是 CMM患者的广泛性比临床诊断的MAR的发病率所建议的，并且 靶向和免疫疗法的使用增加可能会增加3月的风险。拟议的项目旨在 确定CMM患者中TRPM1自身抗体的发生率和次临床MAR的发生率，以及它是否是否 根据治疗而变化。此外，我们旨在确定哪些TRPM1 mRNA剪接变体产生 免疫反应性TRPM1多肽，并测试我们的假设，即这些多肽存在于CMM中 来自TRPM1自身抗体和次临床MAR的患者的标本，与下降有关 miR-211的调节。 因此，我们将对MAR潜在的细胞机制产生新的见解，这可能是进一步的 一般来说，与副肿瘤自身免疫性疾病有关。这项研究的潜在应用包括 开发预后/诊断测试，可用于评估CMM患者的风险 MAR和肿瘤转移。