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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（由申请方提供）：慢性炎症促进上覆上皮细胞的DNA损伤，通常与肿瘤性疾病相关。此外，上皮组织的DNA损伤导致许多促进炎症反应的细胞因子和趋化因子的释放。特别地，导致细胞衰老的持续DNA损伤反应（PDDR）在产生促炎介质的持续来源方面特别有效;这种反应被称为衰老相关分泌表型（SASP）。因此，似乎合理的是，可能发生DNA损伤/SASP和炎症的自我延续循环，这将导致上覆上皮中持续的突变压力。我们建议的研究将探讨这种联系。这是可能的，由于一种新的生物成像方法，监测真皮微血管血红蛋白（Hgb）的含量。我们发现，充血的焦点地区发生以下应用化学致癌物或紫外线（UV）光小鼠皮肤。充血先于肿瘤形成，发现肿瘤总是发生在这些充血区域，并且这些区域在最初的致癌UV暴露停止后持续存在并扩大。只有充血增加的区域与表皮增生和真皮炎症相关。此外，塞来昔布，一种已知的抗炎剂，被证明可以抑制这些充血区域沿着随后的肿瘤形成。我们假设，最初的致癌暴露在上皮或真皮细胞中引发PDDR偶联的SASP，然后驱动肿瘤发展之前的DNA损伤/真皮炎性血管生成的自我维持循环。我们将利用我们独特的生物成像策略，以两个目标来检验这个想法。在第一个目标中，我们将小鼠暴露在致癌剂量的紫外线下，然后绘制出微血管血液供应的早期变化。然后我们将证实充血区域对应于显微镜下或肉眼可见的肿瘤性疾病之前的炎性血管生成区域。我们还将确定这些充血区是否表现出特征性SASP炎症介质的富集。在第二个目标中，我们将检查覆盖早期充血区域的表皮是否表现出关键DNA损伤调节因子p53的突变增加，p53已知可增强SASP反应。此外，我们将确定是否真皮成纤维细胞或表皮角质形成细胞在早期充血灶表现出衰老标志物，异染色质蛋白1g（HP 1g），双链DNA断裂，gH 2AX和p53 BP 1的标志物。此外，使用转基因小鼠模型（大蓝小鼠），我们将确定充血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存在。在这两个目标中，我们将研究两种抗炎药（塞来昔布和CXCR 2受体拮抗剂）抑制充血灶形成的能力，以及炎症、衰老和表皮突变压力增加的相关特征。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。使用一种新的生物成像工具，我们将研究一种新的致癌模型，这种模型可能会导致新的化学预防或治疗靶点，并提供一种潜在的新方法，用于可视化真皮和表皮的癌前病变。