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and 2 for NRASQ61 R pigment models, the 2"d most common human nevus and melanoma oncogene, to complement our extensive unpublished data for BRAFveooE, Several small molecule approaches will be tested to potentially mitigate pheomelanin-induced melanoma risk including induction of dark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.

抽象的 人类皮肤光谱通常以1（红色）至6（深色本构色素）的梯度进行描述 与紫外线敏感性和黑色素瘤的风险相关，与该梯度平行的是Nevi（摩尔）的增加 从较暗到较轻的光型，这种梯度在可见的nevi上突然掉落在光型1（redhaired）上 出乎意料的是罕见，我们假设并在鼠模型中进行了验证，即Brafveooe_诱导了Nevi 红毛小鼠“看不见”，但实际上与遗传匹配的黑 小鼠，由于缺乏黑色的依美酸酯，它们在临床上是无法使用的，但很容易通过荧光识别 标记，并与自发的黑色素瘤转化和UVA诱导有关 黑色素瘤在红毛小鼠中的风险，这种黑色素瘤风险被追溯到红色色素，因为“白化红色” 小鼠缺乏所有色素，并受到自发（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“无形” Nevi和黑色素瘤生成是 提议在NRASQ61的目标1和2中进行研究 r色素模型，2“最常见的人类蓝色和 黑色素瘤癌，为了补充我们的大量未发表的brafveooe数据，几个小分子 将测试方法以减轻苯烷蛋白诱导的黑色素瘤风险，包括诱导黑暗 Eumelanin合成，一个这样的例子已经被认为是“揭示”“无形” nevusbearing中的可见病变 另外，红毛小鼠的荧光奈维（Nevi 从皮肤和转录术进行了审查，以机械学剖析途径和基因 （包括氧化还原），介导白皮个体中黑色素瘤风险升高的人，只有少数 黑色素瘤来自先前存在的Nevi，因此我们使用模型检查NEVI和整体黑色素瘤风险， 我们还发现，帕金森氏病L-DOPA显着提高了苯烷素的合成 在红发中，与多巴胺前体分开，l-dopa巧合的是 黑色素生物合成，帕金森氏病和黑色素瘤长期以来彼此相关，但 缺乏机械解释，我们观察到低剂量L-DOPA显着提高了黑色素瘤的风险 brafveooe红毛，但在白化红色的小鼠模型（不能产生芬氏素或eumelanin）中，AIM 3将在NRAS061R红毛模型中测试L-DOPA的黑色素瘤因果关系，局部皮肤是否变暗 修改BRAFVEOE已经观察到的增强的黑色素瘤风险，最后，AIM 4将检查假设 ITF调节抗氧化剂途径的表达，该途径包括控制的酶 减少了NADPH和谷胱甘肽键因子缓冲黑素细胞氧化应激，一种酶，一种 线粒体酶NNT最近显示用于调节黑素细胞氧化还原和黑色素体分化， 我们将测试证据表明NNT是M ITF的转录目标，并在功能上审查了新近识别 NNT中的序列变体，由NCI合作者提名为人类的候选家族性黑色素瘤基因。