MITF from control of pigmentation to melanoma risk

MITF 从控制色素沉着到黑色素瘤风险

• 批准号: 10828041
• 负责人: DAVID E FISHER
• 金额: $ 9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10828041
• 关键词: Pigmentation physiologic function; Risk; melanoma

Abstract Human skin phototypes are routinely described in a gradient of 1 (redhaired) to 6 (dark constitutive pigment) which correlates with UV sensitivity and risk of melanoma, Parallel to this gradient is the increase of nevi (moles) from darker to lighter phototypes, a gradient which abruptly drops at phototype 1 (redhaired) where visible nevi are unexpectedly rare, We hypothesized, and verified in murine models, that BRAFveooE_ induced nevi in redhaired mice are "invisible" but actually significantly more abundant compared to genetically matched black mice, They are clinically inapparent due to lack of dark eumelanin, but are easily identified via fluorescence tagging, and associated with profoundly elevated spontaneous melanoma transformation and UVA-induced melanoma risk in redhaired mice, This melanoma risk was traced to red pigment because "albino-redhaired" mice lack all pigment and are protected from either spontaneous (previously published), UVA-induced, or peroxide-induced melanoma, Spontaneous and UVA-induced "invisible" nevi and melanoma-genesis are proposed for study in Aims 1 and 2 for NRASQ61 R pigment models, the 2"d most common human nevus and melanoma oncogene, to complement our extensive unpublished data for BRAFveooE, Several small molecule approaches will be tested to potentially mitigate pheomelanin-induced melanoma risk including induction of dark eumelanin synthesis, One such example was already seen to "reveal" visible lesions in the "invisible" nevusbearing redhaired mice, In addition, the fluorescent nevi, engineered into isogenic pigment backgrounds, will be flow-sorted from skin and transcriptomically scrutinized to mechanistically dissect the pathways and genes (including redox) that mediate the elevated melanoma risk among fair skinned individuals, Only a minority of melanomas arise from pre-existing nevi, so we use our models to examine both nevi and overall melanoma risk, We also discovered that the Parkinson's Disease therapy L-Dopa significantly elevates pheomelanin synthesis in redheads, Separate from being a dopamine precursor, L-Dopa is coincidentally a chemical intermediate in melanin biosynthesis, Parkinson's Disease and melanoma have long been associated with one another, but lacking a mechanistic explanation, We observed that low dose L-Dopa significantly elevates melanoma risk in BRAFveooE redhaired, but not in albino-red mouse models (which cannot make pheomelanin or eumelanin), Aim 3 will test L-Dopa's melanoma causality in NRAS061R redhaired models and whether topical skin darkening may modify the enhanced melanoma risk already observed for BRAFveooE, Finally, Aim 4 will examine the hypothesis that M ITF regulates expression of an anti-oxidant pathway which includes enzymes controlling regeneration of reduced NADPH and glutathione-key factors buffering melanocyte oxidative stress, One such enzyme, the mitochondrial enzyme NNT, was recently shown to modulate melanocyte redox and melanosome differentiation, We will test evidence that NNT is a transcriptional target of M ITF and functionally scrutinize a newly identified sequence variant in NNT, nominated by NCI collaborators as a candidate familial melanoma gene in humans.

摘要 人类皮肤光型通常描述为1（红发）至6（深色组成色素）的梯度 与紫外线敏感度和黑色素瘤风险相关，与此梯度平行的是痣（痣）的增加 从较暗到较亮的光型，在光型1（红发）处突然下降的梯度， 出乎意料的罕见，我们假设，并在小鼠模型中证实，BRAFveooE_诱导痣， 红毛老鼠是“看不见的”，但实际上比基因匹配的黑毛老鼠数量要多得多。 由于缺乏深色真黑素，它们在临床上不明显，但很容易通过荧光识别 标签，并与高度升高的自发性黑色素瘤转化和UVA诱导的 这种黑色素瘤的风险被追溯到红色素，因为“白化红毛” 小鼠缺乏所有的色素，并受到保护，无论是自发的（以前发表），UVA诱导，或 过氧化物诱导的黑色素瘤、自发性和UVA诱导的“隐形”痣和黑色素瘤发生是 建议在NRASQ 61的目标1和2中进行研究 R色素模型，2D最常见的人类痣和 黑色素瘤癌基因，以补充我们广泛的未发表的数据BRAFveooE，几个小分子 将测试可能减轻褐黑素诱导的黑色素瘤风险的方法， 真黑素的合成，一个这样的例子已经被认为是“揭示”可见病变的“不可见的”痣 此外，荧光痣，工程到同基因色素背景，将是 从皮肤上进行流式分选，并进行转录组学检查， （包括氧化还原），介导皮肤白皙个体中黑色素瘤风险升高，只有少数 黑色素瘤由先前存在的痣引起，因此我们使用我们的模型来检查痣和整体黑色素瘤风险， 我们还发现，帕金森病治疗L-多巴显着提高了褐黑素的合成 在红头发的人中，左旋多巴与多巴胺的前体不同，它碰巧是一种化学中间体， 黑色素生物合成、帕金森病和黑色素瘤长期以来一直相互关联，但 由于缺乏机制上的解释，我们观察到低剂量的左旋多巴显著提高了黑色素瘤的风险， BRAFveooE红毛，但在白化红小鼠模型（不能产生褐黑素或真黑素）中没有，Aim 3将在NRAS 061 R红发模型中测试L-多巴的黑色素瘤因果关系，以及局部皮肤变黑是否可能 修改已经观察到的BRAFveooE增加的黑色素瘤风险，最后，目标4将检验假设 MITF调节抗氧化途径的表达，该途径包括控制再生的酶， 还原型NADPH和谷胱甘肽-缓冲黑素细胞氧化应激的关键因子， 线粒体酶NNT，最近显示调节黑素细胞氧化还原和黑素体分化， 我们将测试NNT是M ITF的转录靶点的证据，并从功能上仔细检查新发现的 NNT中的一个序列变异，被NCI合作者提名为人类家族性黑色素瘤的候选基因。