Characterization and Modulation of Proteins Involved in Sulfur Mustard Vesication
Abstract
Sulfar mustard (SM) causes blisters in the skin through a series of cellular changes that we are beginning to identify. In the last year, we found a major role for Ca(2+) and calmodulin in the induction of differentiation in human keratinocytes in response to SM. We also obtained the unexpected results that SM induces markers of apoptosis, and that this process also proceeds via a Ca(2+)-calmodulin-dependent pathway. In addition, we found that SM-induced apoptosis was also mediated by a FADD-dependent pathway which induces caspase activation. The involvement of such varied molecules as Ca(2+), calmodulin, and FADD suggests a complex network involved in SM-induced dffferentiation and apoptosis. However, in our progress to date, we have found that blocking any one of these upstream signals can inhibit terminal differentiation or apoptosis, indicating that these molecular pathways are potential targets for therapeutic intervention. We will continue to modulate the expression and activation of calmodulin and FADD, and thus the differentiation and apoptotic pathways in cultured keratinocytes and grafted epidermis to alter SM toxicity. In addition, we will establish lines of transgenic mice that express antisense to CAM or a dominant-negative inhibitor of the FADD pathway in order to further study their roles in SM vesication in intact animals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1998
- Accession Number
- ADA366664
Entities
People
- Dean S. Rosenthal
Organizations
- Georgetown University