Sign
out: Renal.
Research Interests:
A single layer of epithelial cells
separates us from the harmful effects of inhaled pathogens
and environmental toxic agents. Tight junctions determine
the integrity, barrier function and polarity of this
cell layer. Should the cellular barrier be breached,
the immune system must then distinguish innocuous
from pathogenic antigens. Dendritic cells are key
to this process.
Tight junctions:
Our laboratory examines the molecular composition
and regulation of tight junctions as they pertain
to the permeability properties of the lung. These
studies utilize cultured cells and rodent animal models.
Using inducible expression systems, we examined the
contribution of occludin and claudin-1 to the barrier
function of cultured epithelial cells. More recently,
using siRNA to suppress occludin expression by >95%
we found that occludin transduces signals from neighboring
apoptotic cells to the actin cytoskeleton via RhoA.
In further studies, using cholesterol depleting agents
combined with differential centrifugation and density
gradients, we observed that the integral tight junction
proteins appear to segregate into two classes: those
whose physical properties are cholesterol dependent
(occludin, claudin-2 and –3) and those that
are cholesterol independent (claudin-1, -4 and –7).
Defining the molecular composition of tight junctions
is key to understanding the barrier function of epithelial
cells, and to devising strategies that prevent these
proteins from serving as portals of entry to a variety
of pathogens.
Dendritic cells:
A second major goal of our laboratory is to examine
the biology of dendritic cells in the lung. These
important antigen-presenting cells are intercalated
between epithelial cells of airways and in the interstitium
of the lung. We have shown that dendritic cell precursors
are enriched in the pulmonary vasculature, they are
involved in the initiation of granulomatous inflammation,
they engulf inhaled pathogens and transport them to
local lymph nodes where they initiate an immune response.
Using a mouse tracheal epithelial cell line in an
in vitro chemotaxis assay, we have shown that dendritic
cells form transient tight junctions in order to maintain
the epithelial barrier. The ability of dendritic cells
to migrate through the interstitium is dependent on
expression of matrix metalloproteases (MMP), a process
that we examine in selected MMP null mice. Elucidating
these processes are key to understanding the defense
mechanisms that operate to protect the lung from environmental
pathogens.
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