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.
|Effective start/end date||8/13/12 → 7/31/15|
- National Institutes of Health: $187,575.00
- National Institutes of Health: $244,720.00
Double-Stranded DNA Breaks
- Environmental Science(all)