Characterization of persistent hyperemic foci and their role in photocarcinogenes

持续充血病灶的特征及其在光致癌物中的作用

基本信息

批准号：
8385329
负责人：
RAYMOND L KONGER
金额：
$ 24.47万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-13 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385329
关键词：
Aging Animals Anti-Inflammatory Agents Appearance Area CDKN2A gene Carcinogen exposure Carcinogens Cell Aging Cells Characteristics Chemicals Chemopreventive Agent Chronic Clinical Coupled DNA DNA Damage DNA Double Strand Break Dermal Dermis Development Disease Dose Epidermis Epithelial Epithelium Excision Exhibits Fibroblasts Figs - dietary Frequencies Future Gene Mutation Hemoglobin Heterochromatin Human Hyperemia Hyperplasia Image Imaging technology Inbred HRS Mice Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-8B Receptor Lead Left Lesion Life Link Malignant Neoplasms Maps Measurement Measures Mediating Methods Microscopic Modeling Monitor Mus Mutation Oxidative Stress Phenotype Premalignant Change Probability Production Proteins Protocols documentation Role Sampling Shuttle Vectors Signal Transduction Skin Skin Cancer Source Sun Exposure The Sun Time Tissues Transgenic Mice Ultraviolet Rays Vascular blood supply angiogenesis bioimaging carcinogenesis celecoxib chemical carcinogen chemokine cytokine high risk insight keratinocyte mouse model neoplastic novel novel strategies oxidative DNA damage pressure response senescence spatiotemporal therapeutic target therapy design tool tumor tumorigenesis ultraviolet

项目摘要

DESCRIPTION (provided by applicant): Chronic inflammation promotes DNA damage to overlying epithelium and is frequently associated with neoplastic disease. In addition, DNA damage to epithelial tissues results in the release of a number of cytokines and chemokines that promote an inflammatory response. In particular, a persistent DNA damage response (PDDR) leading to cellular senescence is particularly potent in producing a sustained source of pro- inflammatory mediators; this response has been called the senescence associated secretory phenotype (SASP). It would therefore seem reasonable that a self-perpetuating cycle of DNA damage/SASP and inflammation could occur that would lead to continuing mutation pressure in overlying epithelium. Our proposed studies will examine this linkage. This is possible due to a novel bioimaging approach that monitors dermal microvascular hemoglobin (Hgb) content. We show that focal areas of hyperemia occur following the application of chemical carcinogens or ultraviolet (UV) light to mouse skin. Hyperemia preceded tumor formation, tumors were found to invariably occur in these areas of hyperemia, and these areas were seen to persist and expand following the cessation of an initial carcinogenic UV exposure. Only areas with increased hyperemia were associated with epidermal hyperplasia and dermal inflammation. Moreover, celecoxib, a known anti-inflammatory agent, was shown to suppress these areas of hyperemia along with subsequent tumor formation. We hypothesize that initial carcinogenic exposures elicit a PDDR coupled SASP in epithelial or dermal cells that then drive a self- perpetuating cycle of DNA damage/dermal inflammatory angiogenesis that precedes neoplastic development. We will utilize our unique bioimaging strategy to examine this idea in two aims. In the first aim, we will expose mice to a carcinogenic dose of UV of limited duration, then map out early changes in microvascular blood supply. We will then verify that hyperemic areas correspond to zones of inflammatory angiogenesis that precede microscopic or macroscopic neoplastic disease. We will also determine whether these hyperemic zones exhibit enrichment for characteristic SASP inflammatory mediators. In the second aim, we will examine whether the epidermis overlying early hyperemic areas exhibit increased mutations of the key DNA damage regulator, p53, which is known to augment the SASP response. Moreover, we will determine whether dermal fibroblasts or epidermal keratinocytes in early hyperemic foci exhibit a senescence marker, heterochromatin protein 1g (HP1g), and markers of double stranded DNA breaks, gH2AX and p53BP1. In addition, using a transgenic mouse model (Big Blue mice), we will determine whether hyperemic areas are associated with increased epidermal mutation frequency and whether this mutation pressure persists in the absence of further UV exposures. In both aims, we will examine the capacity of two anti-inflammatory agents (celecoxib and a CXCR2 receptor antagonist) to suppress the formation of hyperemic foci and the associated features of inflammation, senescence and increased epidermal mutation pressure. PUBLIC HEALTH RELEVANCE: Skin cancer is by far the most common malignancy in humans. Using a novel bioimaging tool, we will examine a new model of carcinogenesis that potentially could lead to new chemopreventive or therapeutic targets and provide a potential new method for visualizing premalignant changes to the dermis and epidermis.

描述（由申请人提供）：慢性炎症会促进DNA损伤对上层上皮，并且经常与肿瘤疾病有关。此外，DNA对上皮组织的损伤导致许多细胞因子和趋化因子释放，这些因子促进炎症反应。特别是，导致细胞衰老的持续性DNA损伤反应（PDDR）在产生持续的炎性介体来源时尤其有效。该反应称为衰老相关的分泌表型（SASP）。因此，可能会发生DNA损伤/SASP和炎症的自我持续周期，这可能会导致上皮上皮的持续突变压力。我们提出的研究将研究这种联系。这是由于一种新型的生物成像方法，可以监视皮肤微血管血红蛋白（HGB）含量。我们表明，在应用化学致癌物或紫外线（UV）光在小鼠皮肤上的光中，充血的焦点区域发生。充血性肿瘤形成之前，发现肿瘤总是在这些充血区域发生，并且在停止初始致癌紫外线暴露后，这些区域被认为持续并扩展。只有高血症增加的区域与表皮增生和皮肤炎症有关。此外，已知的一种已知抗炎剂Celecoxib被证明可抑制这些充血区域以及随后的肿瘤形成。我们假设最初的致癌暴露会引起上皮或真皮细胞中的PDDR耦合SASP，然后驱动DNA损伤/真皮炎性血管生成的自永久循环，该周期在肿瘤发育之前。我们将利用我们独特的生物成像策略以两个目标来研究这一想法。在第一个目标中，我们将使小鼠接触持续时间有限的紫外线的致癌剂量，然后绘制出微血管血液供应的早期变化。然后，我们将验证多血症区域对应于微观或宏观肿瘤疾病之前的炎性血管生成区域。我们还将确定这些高血压区是否表现出对特征SASP炎症介质的富集。在第二个目标中，我们将检查表皮上覆盖的早期血症区域是否表现出更多的DNA损伤调节剂P53的突变，该突变已知可以增强SASP反应。此外，我们将确定早期高血症灶中的皮肤成纤维细胞或表皮角质形成细胞是否表现出衰老标记物，异染色质蛋白1g（HP1G）以及双滞留DNA DNA断裂，GH2AX和P53BP1的标记。此外，使用转基因小鼠模型（大蓝色小鼠），我们将确定高血症区域是否与表皮突变频率增加有关，以及在没有进一步紫外线暴露的情况下，这种突变压力是否持续。在这两个目标中，我们都将研究两种抗炎剂（塞来昔布和CXCR2受体拮抗剂）的能力，以抑制高血症灶的形成以及炎症，衰老和表皮突变压力的相关特征。公共卫生相关性：皮肤癌是迄今为止人类最常见的恶性肿瘤。使用新型的生物成像工具，我们将研究一种新的癌变模型，该模型可能会导致新的化学预防或治疗靶标，并为可视化真皮和表皮的前态度变化提供潜在的新方法。