Accession Number:

ADA416067

Title:

Characterization and Modulation of Proteins Involved in Sulfur Mustard Vesication

Descriptive Note:

Final rept. 1 May 2000-30 Apr 2003

Corporate Author:

GEORGETOWN UNIV WASHINGTON DC

Personal Author(s):

Report Date:

2003-05-01

Pagination or Media Count:

65.0

Abstract:

To develop medical countermeasures for exposure of military personnel and civilians, we defined the molecular series of events leading to SM vesication. We made significant headway in elucidating several important pathways by which SM induces cell death in cultured keratinocytes and dermal fibroblasts, as well as in intact mouse and grafted human skin. During the granting period, we found that SM induces markers of terminal differentiation as well as apoptosis in NHEK. We observed activation of a death receptor pathway for apoptosis, in which Fas receptor and Fas ligand FasL play a role, as well as a calmodulin CaMBcl-2-mediated mitochondrial apoptotic pathway. Following SM treatment, keratinocytes significantly unregulated levels of both Fas receptor and FasL, which is soon followed by the rapid activation of the upstream caspase-8, mediated by recruitment of the adaptor protein FADD. This is followed by the activation of the executioner caspase-3, -6, and -7. Retroviral constructs expressing a dominant-negative FADD FADD-DN, as well as antisense to CaM were constructed to block each of the apoptotic pathways. Keratinocytes with reduced levels of CaM or FADD signaling were more resistant to SM-induced PARP cleavage and processing of caspases-3, -6, -7, and -8 into their active forms. Significantly, we have found that altering these pathways in human skin grafted onto nude mice reduces vesication and tissue injury in response to SM. These results indicate that these pathways are excellent targets for therapeutic intervention to reduce SM injury.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Chemical, Biological and Radiological Warfare

Distribution Statement:

APPROVED FOR PUBLIC RELEASE