黑色素瘤相关色素基因MC1R对多巴胺能神经元生存调控的细胞定位

Abstract: The positive, bidirectional association between Parkinson’s disease (PD), one of the most common neurodegenerative disease and malignant melanoma (MM), one of the most deadly skin cancers has been consistently demonstrated since the 1970s. However, the underlying mechanisms remain unknown. Our collaborative team initially reported in two large perspective cohorts an increased risk for PD in individuals with red hair. Further analysis indicated an increased PD risk among individuals carrying a loss-of-function variant of melanocortin 1 receptor gene (MC1R). MC1R in melanocytes controls pigmentation by facilitating dark eumelanin production. Loss-of-function MC1R polymorphisms are associated with red hair, fair skin, and high risk of developing MM. Our recent findings demonstrated in mice a protective role of MC1R in the nigrostriatal dopaminergeric system, suggesting MC1R as potential biological basis for the PD-MM link. The overall goal of the proposed study is to address the specific role of MC1R in melanocytes and that of MC1R in dopaminergic neurons. Cre-loxP system will be employed to conditionally knockout MC1R in melanocytes and in dopaminergic neurons discretely to test the hypothesis that MC1R in melanocytes is required for maintenance and defense of the nigrostriatal dopaminergic system (hypothesis 1) or rather it is MC1R in dopaminergic neurons that is indispensable (hypothesis 2). The results from the proposed study will form the firm foundation for further investigations exploring downstream events mediating the MC1R dopaminergic influences with potential for high impact on future development of targeting MC1R as a novel therapeutic strategy for PD. The insight gained from the proposed project will also shed light on our understanding of virtually unexplored relationship between melanocytes and the nigrostriatal dopaminergic system and MC1R basis of the melanoma-PD link.

自70年代起，流行病学研究便不断证实帕金森病（PD）与恶性黑色素瘤（MM）发病的交互易感性，但对其可能机制始终未有解答。我们合作团队此前报道了MM高危红发人群的PD发病风险也增加，继而追踪到决定体表发肤颜色、与MM密切相关的色素基因黑素皮质素受体1(MC1R)变异会导致PD发病风险增高。本课题组新近在小鼠中进一步证实MC1R调控多巴胺神经元生存，首次提供了MC1R作为PD-MM交互发病生物学基础的实验证据。但这一调控作用是由周围体表色素细胞中的MC1R介导，还是中枢神经系统多巴胺能神经元中MC1R的直接作用，尚不清楚。本课题采用Cre-loxP技术分别条件性敲除体表色素细胞和多巴胺能神经元中的MC1R，对调控多巴胺能神经系统的MC1R进行细胞功能定位。研究结果将为MC1R作为多巴胺系统的保护信号和PD治疗靶点提供理论依据和实践指导并进一步推动对此作为PD与MM共同发病因素的跨学科研究。

自70年代起，流行病学研究便不断证实帕金森病（PD）与恶性黑色素瘤（MM）发病的交互易感性，但对其可能机制始终未有解答。我们合作团队此前报道了MM高危红发人群的PD发病风险也增加，继而追踪到决定体表发肤颜色、与MM密切相关的色素基因黑素皮质素受体1(MC1R)变异会导致PD发病风险增高。本课题组新近在小鼠中进一步证实MC1R调控多巴胺神经元生存，首次提供了MC1R作为PD-MM交互发病生物学基础的实验证据。但这一调控作用是由周围体表色素细胞中的MC1R介导，还是中枢神经系统多巴胺能神经元中MC1R的直接作用，尚不清楚。本课题采用Cre-loxP技术分别条件性敲除体表色素细胞和多巴胺能神经元中的MC1R，对调控多巴胺能神经系统的MC1R进行细胞功能定位。研究结果将为MC1R作为多巴胺系统的保护信号和PD治疗靶点提供理论依据和实践指导并进一步推动对此作为PD与MM共同发病因素的跨学科研究。