Cutaneous toxicants occur in the environment, household and office products, chemicals used in industry, labs, agriculture and horticulture. Combined exposures to toxic agents can alter the dose response threshold of an individual agent. In vivo skin immune responses are an excellent system for dissecting alterations in responses to combined exposures. Thus, an allergic contact dermatitis (ACD) skin reaction to a chemical environmental agent alone can be converted into an immune suppressed state if the skin undergoes the chemical exposure in combination with solar radiation. Solar radiation (SR) is an ubiquitous environmental signaling agent often exposing the skin concomitantly with other environmental toxins. Based upon published and preliminary data regarding MAPK family and integrin signaling mechanisms of immunotoxicity, the investigators propose to use a proteomic approach to determine global tissue/cellular responses that are involved in these dramatically polar in vivo outcomes. Their ability to intervene with agents that reverse the immune outcome induced by combined exposure gives them a high likelihood of success in elucidating their hypothesis: SR-induced differential stimulation of MAPK family signaling in keratinocytes and CD11b+ immunocytes results in modulated subsequent signaling by ACD-inducing chemical toxicants and altered immunogenicity of antigen presenting cells. Advances in proteomic technology allow application to the above system via a relatively unbiased, broad identification of changes in the abundance of membrane-bound proteins using isotope coded affinity tagging (ICAT) and phosphoproteins using phosphoprotein isotope-coded affinity tags (PhlAT). A specific focus will be on using bioinformatic approaches currently used for genomic arrays to identify protein networks that undergo change downstream of key molecular interventions known (sCR1) and proposed (MAPK inhibitors) to modify the distinct in vivo outcome associated with combined exposure. These in vivo environmental response mechanisms will be of clinical relevance to risk assessment applications.
