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Biochemical
Pathology
Dr.
Roberts' Homepage
Biochemical
Pathology Staff
Biochemical
Pathology Lab Page
Cell-cell and
cell-matrix interactions are important regulators of normal cell growth
and differentiation and play essential roles in pathological conditions
such as tumor metastasis and infection by pathogens. We are defining
functions of adhesion molecules, their cell surface and matrix receptors,
and the signal transduction pathways that regulate their activities
in specific diseases. These studies will identify new targets for
intervention and could provide a basis for designing novel pharmacological
agents. The primary research projects in my laboratory are: 1) investigating
the role of thrombospondin-1 (TSP1) in regulating tumor progression
and 2) defining the host-pathogen interactions that are required for
establishing disseminated infections by the pathogenic yeast Candida
albicans. These projects are in divergent fields but share a common
goal to define the mechanisms by which cells regulate their interactions
with extracellular matrix. The cross fertilization between these projects
has helped us to make significant contributions to both fields.
Regulation of angiogenesis by thrombospondins.
We are investigating the mechanisms by which TSP1 and TSP2 inhibit angiogenesis and tumor progression. We defined specific domains and peptide sequences that mediate these activities. Stable analogs of inhibitory peptides prevented angiogenesis in several animal models and are being developing for potential therapeutic use. We also identified a pro-angiogenic region in TSP1 and three receptors that mediate this activity. Recombinant regions of TSP1 containing these sequences stimulate rather than inhibit angiogenesis. Thus, we propose that TSP1 should be viewed as a conditional modulator of angiogenesis, wherein endothelial cell responses to TSP1 are qualitatively and quantitatively regulated by their context. We have identified several signals that control how endothelial cells respond to TSP1. Recognition of TSP1 by the integrin a3 b1 in endothelial cells is specifically modulated by VE-cadherin. Two additional TSP1/2-binding integrins were found to be differentially regulated in their expression and function between large vessel and microvascular endothelial cells. Our future goal is to define how opposing signals from these endothelial cell TSP receptors are integrated to control angiogenesis.
We recently identified an important signaling node for the anti-angiogenic activity of TSP1. Physiological levels of nitric oxide stimulate angiogenesis via cGMP signaling. We found that TSP1 potently inhibits this pathway both upstream and downstream of cGMP and that this plays an important role in inhibition of angiogenesis by TSP1. Using functional magnetic resonance imaging, we also found endogenous TSP1 to be a potent regulator of vascular homeostasis in vivo through its antagonism of nitric oxide signaling. This regulation affects vascular tone as well as angiogenesis and is responsible for the negative impact of TSP1 on tissue survival of ischemic injuries. Two TSP1 receptors, CD36 and CD47, mediate its inhibition of cGMP signaling, but only CD47 is necessary for this response. Recently we discovered that therapeutic inhibition of CD47 binding or expression can protect tissues from ischemic injury. We are defining the signaling pathways through which TSP1 modulates cGMP signaling and developing novel approaches to enhance the anti-angiogenic activity of TSP1 using redox-modulating drugs.
Regulation of host colonization and vascular dissemination of Candida
albicans
Candidiasis is
an increasingly common complication of cancer treatment with high
morbidity and mortality. Candidemia has increased tenfold in the past
ten years and now constitutes the third most common cause of positive
blood cultures. Candidemia in neutropenic cancer patients causes septic
shock and multi-organ failure. Because clinical isolates are increasingly
resistant to available antifungal agents, new approaches are needed
to prevent and treat these infections in cancer patients. Our current
studies of the pathogenic yeast C. albicans are based on our discovery
that hemoglobin specifically induces expression of a receptor for
the extracellular matrix protein fibronectin. This response to hemoglobin
is conserved among pathogenic species in the Candida genus but not
other yeasts. Hemoglobin induces adhesion to several host matrix proteins
and to endothelial cell monolayers. Both biochemical and molecular
approaches are being used to identify the matrix receptors induced
on C. albicans. We have identified a hemoglobin-induced cell wall
protein that binds to fibronectin. We have cloned several novel genes
that are specifically induced by hemoglobin. These genes define a
new differentiation pathway by which the pathogen adapts to the vascular
compartment of its host. Understanding the molecular mechanisms for
regulation of this differentiation pathway could lead to new therapeutic
targets to manage infections caused by these organisms.
Recent Publications:
- Pendrak, M. L., et al. J. Biol. Chem. 279:3426-3433, 2004
- Calzada, M. J., et al. Circ. Res. 94: 462-470, 2004
- Isenberg JS, et al, PNAS (2005)
- Zhou L, et al, Oncogene (2006)
- Isenberg JS, et al, J Biol Chem (2006)
- Furrer J, et al, J Med Chem (2006)
- Kuznetsova SA, et al, J Cell Sci (2006)
- Isenberg JS, et al, Blood (2007)
- Roberts DD, et al, Clin Cancer Res (2007)
- Isenberg JS, et al, Circ Res (2007)
- Pendrak ML & Roberts DD, Med Mycol (2007)
- Pendrak ML, et al, Med Mycol (2007)
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