Characterization and Modulation of Proteins Involved in Sulfur Mustard Vesication
Final rept. 16 Sep 1996-15 May 2000
GEORGETOWN UNIV WASHINGTON DC MEDICAL CENTER
Pagination or Media Count:
Sulfur mustard SM causes blisters in the skin through a series of cellular changes that we are beginning to identify. Recently, using chemical inhibitors, we found a major role for Ca2 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 Ca2-calmodulin-dependent pathway. We have extended these studies to show that expression of calmodulin antisense RNA blocks the differentiation and apoptotic response of keratinocytes to SM. In addition, using a dominant-negative inhibitor FADD-DN, we have found that SM-induced apoptosis is also mediated by a FADD-dependent pathway, which induces caspase activation. The involvement of such varied molecules as Ca2, calmodulin, and FADD suggests a complex network involved in SM-induced differentiation and apoptosis. However, in our studies 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. Immortalized keratinocytes stably transfected with FADD-DN form normal epidermis on athymic mice, but have an altered response to SM. We are also currently utilizing retroviral expression vectors expressing calmodulin antisense RNA to modulate the expression of calmodulin, and thus the differentiation and apoptotic pathways in primary keratinocytes and grafted epidermis to alter SM toxicity.
- Anatomy and Physiology
- Chemical, Biological and Radiological Warfare