Assessing the risk of UV-induced skin cancer via non-invasive epidermal sampling

通过无创表皮取样评估紫外线诱发皮肤癌的风险

基本信息

批准号：
8810480
负责人：
Samir S Mitragotri
金额：
$ 23.15万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8810480
关键词：
Accounting Address Age BRAF gene Biological Markers Biopsy Specimen Cancerous Carcinoma Categories Chemistry Clinical Collection Cutaneous DNA DNA Damage DNA Mutational Analysis DNA Sequence Alteration DNA photoproducts Data Development Disease Dose Ensure Environmental Risk Factor Epidermis Frequencies Goals Harvest Hematologic Neoplasms Histology Histopathology Hour Human Inbred HRS Mice Incidence Induced Mutation Kinetics Lesion Libraries Link Liquid substance Malignant Neoplasms Measurement Measures Mechanics Mediating Medical Methodology Methods Modeling Molecular Profiling Molecular Weight Morbidity - disease rate Mosaicism Mutation Mutation Detection Patients Pharmaceutical Preparations Process Productivity Recovery Research Risk Risk Assessment Safety Sampling Skin Skin Cancer Skin Carcinoma Source Structure TP53 gene Technology Testing Thymine Dimers Time Tumor Suppressor Genes UV induced UV induced DNA damage Ultrasonics Ultrasonography Ultraviolet B Radiation Ultraviolet Rays base cancer risk combinatorial cost economic impact exome genome sequencing inhibitor/antagonist irradiation keratinocyte melanoma mortality mouse model next generation sequencing novel peripheral blood public health relevance rapid technique skin squamous cell carcinoma surfactant tool ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): The objective of this study is to develop "a methodology for sampling DNA from skin to assess the risk of UV-induced skin cancer development". Our goal is to establish non-invasive biomarker sampling from skin for a variety of systemic and cutaneous diseases. Here, we will focus on measurement of UV-induced DNA mutations that are linked to all skin cancers, both non-melanoma skin cancers and melanoma alike. Our central hypothesis is that the non- invasive collection and mutational analysis of DNA from clinically-normal skin correlates with the level of risk for skin cancer. We will demonstrate this in a mouse model of UV-induced skin cancer using our novel methods. Our specific aims are: Specific Aim 1: Optimize ultrasound-assisted sampling of DNA from skin. We will first assess the optimal ultrasound (intensity, duty cycle and exposure time) and microdermabrasion (contact roughness and oscillation frequency) parameters to maximize the total amount of DNA extracted from the skin. We will also optimize the chemistry of the sampling medium (liquid used to couple mechanical energy to the skin) to maximize the amount and stability of collected DNA using a combinatorial library of surfactants chosen from four categories (cationic, anionic, zwitterionic and non-ionic surfactants). Our goal is to harvest at least 5 ug DNA per sq. cm of skin and ensure its stability (>80%) for 4 hours. Specific Aim 2: Evaluate the safety of the sampling process. We will perform detailed histopathology assessment of sampled skin to determine the effect of ultrasound on skin structure. Recovery kinetics of skin after sampling will be assessed. Our target is recovery of skin within 7 days based on histology. Specific Aim 3: Validate the use of UV mutational load in skin as a biomarker of skin cancer risk. Using chronically UV-irradiated Hairless mice, we will characterize the burden of UV signature mutations in skin following ultrasonic DNA extraction at multiple time points following irradiation We will test whether DNA collected from chronically UV-exposed skin by ultrasound can be used to measure the UV-induced mutation burden in terms of DNA photoproducts (thymine dimers), UV signature lesions in particular susceptible genes (Tp53, Hras, Kras, Ink4a), and UV signature mutations across the entire exome.

描述（由适用提供）：这项研究的目的是开发“从皮肤中取样DNA的方法来评估紫外线诱导的皮肤癌发育风险”。我们的目标是从皮肤中为各种系统性和皮肤疾病建立非侵入性生物标志物采样。在这里，我们将专注于测量与所有皮肤癌（非黑色素瘤皮肤癌和黑色素瘤）相关的UV诱导的DNA突变。我们的中心假设是，来自临床正常皮肤的DNA的非侵入性收集和突变分析与皮肤癌的风险水平相关。我们将使用我们的新方法在紫外线诱导的皮肤癌的小鼠模型中证明这一点。我们的特定目的是：特定目标1：优化皮肤DNA的超声辅助采样。我们将首先评估最佳超声（强度，占空比和暴露时间）和微磨性（接触粗糙度和振荡频率）参数，以最大程度地提高从皮肤中提取的DNA的总量。我们还将使用从四种类别（阳离子，阴离子，ZWITTRICINIC和非离子表面活性剂）中选择的表面活性剂组合库（用于将DNA的液体（用于将机械能与皮肤搭配到皮肤）的液体的化学性质（用于将机械能与皮肤搭配到皮肤的液体）最大化。我们的目标是每平方英尺的皮肤至少收获5 ug DNA，并确保其稳定性（> 80％）4小时。具体目标2：评估抽样过程的安全性。我们将对采样皮肤进行详细的组织病理学评估，以确定超声对皮肤结构的影响。采样后皮肤的恢复动力学将被评估。我们的目标是基于组织学内7天内的皮肤恢复。特定目标3：验证在皮肤中使用紫外线突变负荷作为皮肤癌风险的生物标志物。 Using chronically UV-irradiated Hairless mice, we will characterize the burn of UV signature mutations in skin following ultrasonic DNA extraction at multiple time points following irradiation We will test whether DNA collected from chronically UV-exposed skin by ultrasound Can be used to measure the UV-induced mutation burn in terms of DNA photoproducts (thymine dimers), UV signature lesions in particular susceptible genes （TP53，HRAS，KRAS，INK4A）和整个外显子的UV签名突变。