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BIOLOGY WORKING GROUPS
Three biology working groups (BWG) will address key questions of
contemporary heart, blood and lung research and provide the interface between
the technology development and applied activities of the Center. The groups
bring together distinguished researchers from the Puget Sound area with the
purpose of identifying novel approaches to address biological problems
utilizing proteomics. The three working groups will focus on:
Macrophage activation
This group recognizes the critical
protective role played by monocyte/macrophage as a primary means of defense
in an inflammatory response through its capacity as the scavenger cell of the
body and its fundamental importance in specific immunity. However,
inflammation also forms the basis of a series of life-threatening and
functionally crippling diseases that includes atherosclerosis and fibrotic
lung diseases. In particular, the activated macrophage can release an
incredible array of proteins that can induce tissue damage, promote the
influx of more leukocytes and cause extensive scarring and fibrosis that can
result in occlusion of blood vessels and lung alveoli. Although a number of
checks and balances prevent this destructive potential from being realized in
normal responses to injury, they are insufficient to block the progressive
destruction in chronic inflammatory diseases. Thus, defining the
comprehensive proteome of an activated macrophage is of primary importance to
identify strategies to regulate the destructive pathways without
significantly impairing protective mechanisms.
Cardiovascular and blood cell development
This group is based
on the insight that different cells in an organism are defined by the
complement of genes that they express. Cell fate choices reflect and require
the initiation of new programs of gene expression (and extinguishing of
others) that once initiated, must be faithfully passed from parental cells to
their progeny. Therefore, to appreciate the complex processes of mammalian
development and potentially apply this knowledge to gene therapy for genetic
disorders, it is essential to understand how a cell determines which genes it
will express. A major unresolved question is how these changes are initiated
and propagated at specific gene loci during development. The goal of this
area of investigation is to use mass spectrometry to interrogate these
changes during the differentiation of specific cardiac and hematopoietic cell
lineages. The development of technological approaches and general models
established from these studies should provide a basis for studying
tissue-specific gene expression at multiple loci, including those of the
macrophage that is the long-term focus of this program.
Signaling
The Signaling Working Group recognizes that changes
in signaling pathways and the composition of signaling complexes are critical
to the initiation of contraction, proliferation, activation, and
apoptosis - processes involved in a variety of cardiovascular
diseases. Many of the same signaling pathways have been implicated in all of
these processes, and yet the stimuli and downstream effectors are distinct.
The proposed studies will focus on the signaling pathways in cardiac myocytes,
vascular smooth muscle, fibroblasts and endothelial cells whose signaling
pathways share many common themes. Hypothesis-driven analysis of signaling
complexes and more discovery-based approaches such as yeast two-hybrid
analysis have demonstrated that critical players in particular signaling
complexes interact directly with diverse groups of proteins, including
protein kinases, kinase anchoring proteins, scaffolding proteins and cell
adhesion molecules. However, definition of these complexes is far from
complete. Particular signaling pathways, such as those associated with
membranes, have been especially difficult to approach experimentally. The
goal of this working group is to try to expand our ability to probe signaling
pathways and complexes by using mass spectrometry to: 1) more completely
define the changes in cellular protein profiles associated with major
physiologic responses; 2) detail the components of specific signaling
complexes and determine how they dynamically change with different physiologic
stimuli; 3) determine the state of phosphorylation of signaling complexes and
changes in the protein phosphorylation profile of proteins in response to
physiologic stimuli; and 4) develop new approaches for examining protein
interactions in signaling pathways highly regulated by their membrane
interactions.
It should be noted that the projects of the BWGs are not directly funded
by the Center. The Center will, however, make capacity for sample processing
available via the HTPF.
BWG Staff
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