MC1R basis of melanoma-Parkinson's link and neuroprotective potential of MC1R

黑色素瘤-帕金森病联系的 MC1R 基础和 MC1R 的神经保护潜力

• 批准号: 10189714
• 负责人: Xiqun Chen
• 金额: $ 35.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189714
• 关键词: Agonist; Alleles; Animal Model; Back; Biological; Brain; Brain Injuries; C57BL/6 Mouse; Cells; Clinical; Cytoprotection; Diagnosis; Discipline; Disease; Dopamine; Enzymes; Epidemiology; Event; Exhibits; Functional disorder; Future; Gene Activation; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Polymorphism; Goals; Hair; Hair Color; Human; Individual; Investigation; Knockout Mice; Laboratories; Link; MPTP Poisoning; Malignant Neoplasms; Melanins; Melanocortin 1 Receptor; Modeling; Monophenol Monooxygenase; Mus; Mutant Strains Mice; Mutation; Outcome; Oxidative Stress; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Pigmentation physiologic function; Pigments; Population; Predisposition; Process; Receptor Gene; Reporting; Resources; Risk; Role; Signal Transduction; Signaling Protein; Skin; Substantia nigra structure; System; Therapeutic; Toxic effect; Tyrosine 3-Monooxygenase; Variant; Wild Type Mouse; afamelanotide; alpha synuclein; clinical investigation; cohort; disorder risk; dopaminergic neuron; epidemiology study; genetic variant; high risk; insight; loss of function; melanoma; mortality; mutant; neuroprotection; neurotoxicity; new therapeutic target; nigrostriatal system; novel; oxidative damage; pheomelanin; skin damage

Project Summary/Abstract Parkinson's disease (PD) patients generally are at lower risk of developing cancers, with one notable exception – melanoma. Individuals with PD are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing PD. This bidirectional link has been observed not only in patients themselves but also in their relatives, suggesting shared biological components of the two seemingly disparate processes. Melanoma is strongly tied to red hair/fair skin, the phenotype of loss-of-function polymorphisms in the melanocortin 1 receptor gene (MC1R). We have previously reported greater PD risk in individuals with red hair color and individuals carrying a redhead MC1R variant. Normally black (C57Bl/6) mice carrying an inactivating mutation of MC1R (MC1Re/e mice) mimic redhead humans, as they display red/yellow pheomelanin pigmentation and pheomelanin-dependent oxidative skin damage and melanoma predisposition. These redhead mice also exhibit oxidative brain damage and dopaminergic deficiency under basal conditions and exacerbated dopaminergic toxicity in models of PD including α-synuclein (α-syn). MC1R is expressed in dopaminergic neurons of the mouse substantia nigra. The presence of MC1R has also been preliminarily demonstrated in the substantia nigra of the human brain, with reduced signal in sporadic PD patients that correlates to loss of dopaminergic neurons. Further, higher PD-associated mortality among redhead individuals has been preliminarily demonstrated in human cohorts. The overall goal of this interdisciplinary project is to further elucidate role of the melanoma-linked MC1R in PD and neuroprotective potential of targeting MC1R by studying animal models and human populations in parallel via three Specific Aims (SAs). SA1 will determine whether red pigmentation is responsible for the redhead dopaminergic deficit and whether MC1R in catecholaminergic cells is required for nigrostriatal dopaminergic integrity. SA2 will determine whether MC1R activation by existing MC1R agonists protects against α-syn neurotoxicity and whether the protection is MC1R-specific. SA3 will analyze whether redhair and melanoma risk MC1R variants are associated with increased risk of developing PD in healthy populations and whether the same variants are associated with faster clinical progression in those who have already been diagnosed with PD. Built on the strength of epidemiological and biological evidence and backed by exceptional expertise across disciplines, the proposed study is expected to establish the biological plausibility of a causal basis for MC1R (and pheomelanin) and PD and therefore to provide insight into PD-melanoma association. Its findings will be of high translational significance with the potential for major impact on PD therapeutics as well as on our understanding of the epidemiology and pathophysiology of PD. .

项目概要/摘要 帕金森病 (PD) 患者一般患癌症的风险较低，但有一个值得注意的例外： 患有 PD 的个体更有可能患上黑色素瘤，而黑色素瘤患者则相反。 这种双向联系不仅在患者本身中而且在患者中也被观察到。 他们的亲戚认为，这两个看似不同的过程具有共同的生物学成分。 黑皮质素 1 受体功能丧失多态性的表型与红发/白皙皮肤密切相关 基因（MC1R）我们之前报道过红色头发和个体的PD风险更高。 携带红发 MC1R 变异体的正常黑色 (C57Bl/6) 小鼠携带 MC1R 失活突变。 （MC1Re/e 小鼠）模仿红发人类，因为它们表现出红色/黄色褐黑素色素沉着和 这些红发小鼠还表现出依赖于褐黑素的氧化性皮肤损伤和黑色素瘤倾向。 基础条件下氧化性脑损伤和多巴胺能缺乏以及多巴胺能加剧 PD 模型中的毒性包括在小鼠多巴胺能神经元中表达的 α-突触核蛋白 (α-syn)。 黑质中也初步证实了MC1R的存在。 人脑，散发性帕金森病患者的信号减弱，这与多巴胺能神经元的丧失相关。 此外，红发个体与 PD 相关的死亡率较高已在 这个跨学科项目的总体目标是进一步阐明与黑色素瘤相关的作用。 通过研究动物模型和人群，了解 MC1R 在 PD 中的作用以及针对 MC1R 的神经保护潜力 通过三个特定目标 (SA) 并行确定红色色素沉着是否是造成这种情况的原因。 红发多巴胺能缺陷以及黑质纹状体是否需要儿茶酚胺能细胞中的 MC1R SA2 将决定现有 MC1R 激动剂激活 MC1R 是否具有保护作用。 针对 α-syn 神经毒性以及保护是否是 MC1R 特异性的 SA3 将分析是否 redhair 和 黑色素瘤风险 MC1R 变异与健康人群患 PD 的风险增加相关 对于那些已经接受过治疗的患者来说，相同的变异是否与更快的临床进展相关？ 诊断为 PD。建立在流行病学和生物学证据的基础上，并有特殊的支持。 跨学科的专业知识，拟议的研究预计将确定因果关系的生物学合理性 MC1R（和褐黑素）和 PD 的基础，因此可以深入了解 PD 与黑色素瘤的关联。 研究结果将具有高度转化意义，有可能对 PD 治疗以及 加深我们对 PD 流行病学和病理生理学的理解。 。