Defining critical aspects of environmental ultraviolet exposure in melanogenesis

描述(由申请人提供)：这一竞争性修订旨在极大地增强我们估计从自我报告中回溯获得的寿命和特定年龄的太阳紫外线(UV)暴露的能力，并增强我们为家长奖开发并正在使用的新型UV暴露指标。除了加强家长奖的科学方法外，这项额外的方法学工作将广泛适用于自家长奖开始以来由调查团队的合作者发起的关于紫外线暴露和疾病结果的其他一些研究。我们之前开发了一种计算寿命和特定年龄的紫外线曝光量的方法。我们现在有机会对照实时紫外线剂量测量来验证该紫外线度量，并使用该信息更好地测量回溯性紫外线暴露，特别是与黑色素瘤相关但不能用当前方法很好测量的极端和间歇性暴露。在这项拟议的研究中，我们的目标是描述推定的紫外线暴露和实时个人紫外线暴露之间的关系：这种关系当然是由太阳暴露行为调节的(并不是所有的人都会因为他们在相同的地理位置而获得相同的紫外线暴露)。对于黑色素瘤来说，一个关键问题是过去间歇性暴露对疾病的影响。目前，间歇性紫外线暴露是通过自我报告活动来衡量的，例如在阳光下度假、日光浴或短期周末暴露。这些自我报告几乎肯定会错误地对间歇性暴露估计进行分类，目前还不清楚哪种衡量标准最能代表间歇性紫外线暴露。我们的紫外线指标测量的是总紫外线，但对于黑色素瘤，我们也想知道可归因于特定波长(粗略地说，UVA和UVB)的总紫外线暴露的成分。我们的剂量计是为了将特定波长的紫外线测量与自我报告的太阳暴露行为相关联而开发的。我们将在家长奖研究人群中从剂量测量中测量紫外线，并使用这些数据来模拟自我报告的测量、我们推算的紫外线度量(这两个指标也可用于回溯数据)和实时紫外线暴露(特别是间歇性和极端曝光，以及UVA和UVB波长的贡献)之间的关系。拟议的研究将进一步加快我们朝着减少暴露评估误差这一中心主题的进展，以确定紫外线暴露对黑色素瘤的真正影响。这一竞争性修订申请符合ARRA下的所有资助标准，既可以加快直接用于母公司赠款和相关科学的科学研究的步伐，也可以加快创造/保留就业机会的速度，这是刺激法案的主要重点。 与公共卫生相关：在全球大多数人群中，黑色素瘤的发病率正在稳步上升，初级预防努力(主要是基于避免中午前后的阳光照射)成效有限。我们的家长奖旨在更好地描述不同波长的太阳紫外线(UV)在没有遗传易感性混浊效应的情况下对黑色素瘤所起的作用，并提供如何通过行为改变实现初级预防的“最干净”图景。这项拟议的研究通过使用也测量特定波长的紫外线的设备，将估算的紫外线暴露(基于自我报告)与来自剂量学的实时紫外线暴露联系起来，从而加强了这些目标。这些剂量学数据将根据自我报告和输入的紫外线数据进行建模，以确定测量与黑色素瘤相关的过去紫外线暴露的变异性的最佳方式，特别是关注当前方法几乎肯定无法准确捕获的间歇性和极端暴露。

DESCRIPTION (provided by applicant): This Competitive Revision aims to greatly enhance our ability to estimate lifetime and age-specific solar ultraviolet (UV) exposures obtained retrospectively from self-report and enhance the novel UV exposure metric that we developed for, and are using in, the Parent Award. As well as enhancing the scientific approach of the Parent Award, this additional methodological work will have wide applicability to a number of other studies of UV exposure and disease outcome that have been initiated since our Parent Award began, by collaborators of the investigative team. We previously developed a method of imputing lifetime and age-specific UV exposure. We now have an opportunity to validate that UV metric against real-time UV dosimetry, and use that information to better measure retrospective UV exposure, especially extreme and intermittent exposures that are relevant to melanoma but not well measured by current methods. In the proposed study, we aim to characterize the relationship between imputed UV exposure and real-time personal UV exposure: that relationship is certainly mediated by sun exposure behavior (not all people will receive the same UV exposure just because they are in the same geographical location). For melanoma, a critical issue is the impact of past intermittent exposure on disease. Currently, intermittent UV exposure is measured by self-report of activities such as vacations in the sun, sun bathing, or short term weekend exposures. These self-reports almost certainly misclassify intermittent exposure estimates, and it is unclear which measure best represents intermittent UV exposure. Our UV metric measures total UV, but for melanoma we also want to know the component of total UV exposure that is attributable to specific wavelengths (crudely, UVA and UVB). Our dosimeters have been developed in order to correlate wavelength-specific UV measures with self-reported sun exposure behavior. We will measure UV from dosimetry in the Parent Award study population, and use those data to model the relationship between self-reported measures, our imputed UV metric (both of which are available for retrospective data also) and real time UV exposure (especially intermittent and extreme exposures, and the contribution of UVA and UVB wavelengths separately). The proposed study will further accelerate our progress towards the central theme of reducing exposure assessment error in order to determine the true effects of UV exposure on melanoma. This Competitive Revision application meets ALL of the criteria for funding under the ARRA, both for accelerating the tempo of scientific research directly for the Parent Grant and for associated science, and for job creation/retention that is the primary focus of the Stimulus Bill. PUBLIC HEALTH RELEVANCE: Melanoma incidence is increasing steadily in most populations worldwide, and primary prevention efforts (largely based on avoiding sun exposure around midday) have had limited success. Our Parent Award aims to better characterize the role of varying wavelengths of solar ultraviolet (UV) on melanoma, in the absence of the muddying effect of genetic susceptibility, and provide the 'cleanest' picture of how to achieve primary prevention through behavior change. The proposed study enhances those aims by relating imputed UV exposures (based on self-report) to real time UV exposure from dosimetry, using devices that also measure wavelength-specific UV. Those dosimetry data will be modeled against self report and imputed UV data to determine the best way to measure variability in past UV exposures that is relevant to melanoma, focusing specifically on intermittent and extreme exposures that current methods almost certainly fail to accurately capture.