• Connor, James (PI)
  • Chorney, Michael J. (PI)
  • Billingsley, Melvin (PI)

Project: Research project

Project Details


The long-term goal of this proposal is to understand the biological role
of the hemochromatosis disease gene, termed HFE, which carries one of the
most common mutations currently known. The objectives are to unravel the
product's functional niche in iron circuitry and to understand the
molecular mechanisms through which it maintains iron balance in
enterocytes and cells of the reticuloendothelial system. HFE is a unique
member of the highly divergent class Ib gene family and as such, its
expression in the mouse appears to be relegated to macrophages and
enterocytes where it presumably exerts its biological effect(s). Unusual
characteristics arising from our preliminary investigations include HFE's
cell-surface expression even in the absence of beta2m and its partial
dependence on TAP transport. In order to understand HFE's biological role,
we have focused on three specific aims related to HFE's structure,
expression (both in vitro and in vivo) and its relationship to intestinal
iron flux and TNF-alpha responsiveness. Specifically, we will determine
the elements required for HFE cell-surface expression (beta2m and TAP) and
will determine the nature of bound self-peptide which, if specific, could
herald a novel mechanism underlying HFE folding and transport. With
respect to expression, we will analyze the kinetics of HFE's intracellular
processing, paying particular attention to both its partial interaction
with additional protein molecules (receptors or transporters) and to its
possible subcellular routing and localization. Emanating from our
preliminary data demonstrating increased HFE staining an a concomitant
increase in intraepithelial lymphocytes staining positive for TNF-alpha in
iron-loaded mice, we will continue to focus on the small intestine
following iron challenge and will attempt to determine TNF-alpha's role in
the maintenance of normal ferrokinetics within the context of control and
knockout mouse model systems. Our hypothesis is that HFE, as part of a
larger complex, undergoes up-regulation in the intestine in response to
iron leading to an increase in macrophages and intestinal TNF-alpha which
is directly related to enterocyte differentiation and iron flux.
Effective start/end date10/1/9812/31/03


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