Molecular Surrogate for Melanoma Prevention

预防黑色素瘤的分子替代品

基本信息

批准号：
7383595
负责人：
GRAHAM S TIMMINS
金额：
$ 7.5万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-27 至 2009-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 60,000 Americans will be diagnosed with Melanoma 2007, of whom 8,000 will die. Yet, melanoma prevention by current sunscreen is ineffective, and chemoprevention in its infancy. Melanin is central to the causation of melanoma. In addition to it protectively absorbing UV, a fraction of this energy results in the formation of reactive melanin-radicals, a process is central to melanoma causation. We therefore propose that measurement of UV induced reactive melanin-radicals (UV-RMR) can provide a mechanistically-based molecular surrogate for melanoma causation, and hence that measuring the decrease in UV-RMR by protective agents will provide a molecular surrogate of melanoma protection. Importantly, the required EPR measurements of UV induced reactive melanin-radicals can be performed in systems ranging from isolated melanin, to in vivo and in situ in melanocytes in skin. Thus, our overall hypothesis is that: The ability of protective agents to inhibit UV-induced reactive melanin radical formation provides a mechanistically-based molecular surrogate to assay melanoma prevention interventions. We propose using this technique to study two complementary strategies of melanoma prevention, one based upon UV screening by sunscreen agents to prevent UV-RMR production, the other based upon novel scavenging of UV-RMR before these can cause biological damage. Specific Aim 1. Correlate decreased UV-RMR by sunscreens in M. domestica, with decreases in oxidative DNA damage in vivo. This correlation will provide a rigorous test of our hypothesis that inhibition of UV-RMR can provide a surrogate of melanoma prevention. Specific Aim 2. Develop an assay for chemoprevention of melanoma by screening a select library of com- pounds for scavenging of UV-RMR by measuring both steady state reductions in UV-RMR and rates of UV-RMR decay, using isolated melanins and cultured melanocytes as models. Correlate scavenging of UV-RMR with decreases in oxidative damage in melanocytes. This proposal uses the PI's unique experience to provide a new mechanistic surrogate for melanoma prevention by both physical and chemopreventive agents that can potentially be applied clinically with in vivo EPR. Upon successful completion, we plan to perform in vivo melanoma prevention trials of sunscreen and UV-RMR scavenging chemopreventive agents in our animal models, and then in susceptible patient populations.

描述（由申请人提供）：有60,000名美国人将被诊断出患有黑色素瘤2007，其中8,000人将死亡。然而，当前防晒霜预防黑色素瘤是无效的，并且在其婴儿期进行化学预防。黑色素是黑色素瘤因果关系的核心。除了保护性吸收紫外线外，这种能量的一部分还会导致反应性黑色素 - 自由基的形成，这是黑色素瘤因果关系的核心。因此，我们提出，测量UV诱导的反应性黑色素 - 自由基（UV-RMR）可以提供基于机械的基于机械性的分子替代物来使黑色素瘤因果关系，因此测量保护剂的uv-RMR降低将提供一种可提供的uv-rmr。。重要的是，可以在从孤立的黑色素到体内和皮肤中黑素细胞中的系统中进行紫外线诱导的反应性黑色素 - 自由基所需的EPR测量。因此，我们的总体假设是：保护剂抑制紫外线诱导的反应性黑色素自由基形成的能力为测定黑色素瘤预防干预提供了一种基于机械的分子替代物。我们建议使用该技术研究预防黑色素瘤的两种互补策略，一种基于防晒霜的紫外线筛选以防止UV-RMR的产生，另一种基于对UV-RMR的新清除，然后才会造成生物学损害。特定的目标1。在himea中，防晒霜降低了UV-RMR，体内氧化DNA损伤的降低。这种相关性将对我们的假设进行严格的检验，即抑制UV-RMR可以提供预防黑色素瘤的替代物。具体目的2。通过筛选精选的库中的库中的分析库来清除UV-RMR，从作为型号。将UV-RMR的清除与黑色素细胞中氧化损伤的减少相关。该提案利用PI的独特经验为物理和化学预防剂提供了一种新的机械替代性，可用于预防黑色素瘤，并有可能在临床上使用体内EPR应用。成功完成后，我们计划对我们的动物模型，然后在易感患者人群中进行防晒和UV-RMR清除化学预防剂的预防体内黑色素瘤试验。