ROLE OF AHR/ARNT SIGNALING ON MATRIX REMODELING IN SKIN

Project Details

Description

DESCRIPTION (Adapted from the Candidate's Abstract)
TCDD exposure leads to severe skin lesions known as chloracne. These lesions
are characterized by hyperproliferation, hyperdifferentiation, and abnormal
migration of keratinocytes in the stratified squamous epithelia. It is
unclear how TCDD exposure leads to the skin pathology. Most of the studies on
the molecular mechanisms of TCDD function have focused on the ligand-activated
transcription factor AhR/Arnt. Binding of TCDD to AhR initiates
heterodimerization with Arnt, and ultimately alters transcription through
binding of this complex to specific sites (XRES) in the 5' regions of AhR
responsive genes. TCDD target genes identified include the Phase I and Phase
II detoxifying enzymes, as well as cytokines (TGF-B, IL-1B), transcription
factors (Fos, Jun), and an extracellular matrix remodeling inhibitory proteins
(PAI-2). Metabolism of the extracellular matrix is required in situations
that require tissue remodeling or cell migration, such as wound healing. The
majority of the matrix degradation is accomplished through the activity of
members of the matrix metalloproteinase (MMP) family. A transcription factor
database search identified two potential XRE sites in the 5' region of MMP-1,
and preliminary results demonstrate that MMP-1 MRNA levels increase upon TCDD
treatment of keratinocytes. This data suggests a link between TCDD/AhR/Arnt
and matrix remodeling. The candidate is currently a post-doctoral fellow in
the laboratory of Dr. B. L. Allen-Hoffmann at the University of Wisconsin-
Madison, where her project is to generate a tissue specific knockout mouse of
AhR in stratified squamous epithelia to study the effects of AhR loss on skin
structure and differentiation. The goal of this proposal is to study the skin
pathology resulting from TCDD exposure in intact tissue, and determine the
role of the AhR/Arnt pathway on MMPs and their inhibitors, the TIMPS, into the
affected skin. Therefore the specific aims of this proposal are: (1) create
a mouse model, using the Cre/loxP recombination system of bacteriophage P1, to
conditionally knock out the Arnt gene in the replicating keratinocytes of
murine skin. Use this mouse model, along with the AhR tissue specific
knockout, to study the effect of AhR and Arnt loss on MMP/TIMP expression and
TCDD skin pathologies. (2) Use keratinocytes in an organotypic cell culture
system to study the effect of TCDD on tissue architecture and gene expression
of MMPs/TIMPS.
StatusFinished
Effective start/end date6/1/005/31/04

Funding

  • National Institute of Environmental Health Sciences: $80,165.00
  • National Institute of Environmental Health Sciences: $106,245.00
  • National Institute of Environmental Health Sciences: $106,062.00

ASJC

  • Cell Biology

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