Cell motility and proliferation are integral components of the processes that occur during inflammation, angiogenesis and organogenesis. Interactions of the extracellular matrix with specific cell-associated receptors are important in the regulation of these cell behaviors. Hyaluronan (hyaluronic acid, HA) is a ubiquitous glycosaminoglycan whose physico-chemical properties predict a hydrophilic molecule that provides structural integrity to the intercellular space. However, HA has been associated with cell movement and growth in a wide variety of cells, as well in homeostatic and disease processes. Interaction with specific receptors is responsible for the biologic actions of HA and two cell-surface receptors have thus far been cloned, namely CD44 and RHAMM (Receptor for HA-Mediated Motility). While RHAMM and CD44 are molecularly distinct, they both have charge domains that promote HA-binding. Synthetic peptides mimicking this HA-binding motif inhibit receptor-mediated functions by sequestering HA.
My laboratory is studying the role of HA and its receptors in a variety of models of tissue injury, in particular the response to lung injury. We have demonstrated that RHAMM and HA expression is increased in inflammatory cells accumulating in the lung after intratracheal bleomycin in rodents and that RHAMM: HA interactions regulate macrophage motility in vitro. Administration of HA-binding peptide or anti-RHAMM antibody to bleomycin-injured animals results in decreased inflammation, respiratory distress and fibrosis. These responses are also being analyzed in transgenic animals with targeted disruption of specific genes, in particular CD44 and RHAMM. We are also interested in the molecular signals arising from oxidative and nitrative stresses after injury that initiate the inflammatory cascade and are exploring the effects of potential blockers of these processes. Further, we are examining the role of inflammation in surfactant protein gene expression after bleomycin injury, as well as correlating our findings with samples obtained from preterm infants at risk of developing bronchopulmonary dysplasia (BPD).
Another major focus is the cellular and molecular signals that regulate angiogenesis in the lung during alveolar formation. Decreased alveolization is a major feature of lung injury and understanding of the mechanisms of normal alveolization will give us insight as to potential therapeutic interventions to augment alveolization. We are studying endothelial cell behavior in vitro and animal models of decreased alveolar septation (hypoxia and hormonal regulation of alveogenesis) to determine the regulation of this intricate process.
The laboratory is also studying the signaling mechanisms mediated by HA and its receptors within lipid rafts that regulate macrophage, endothelial and vascular smooth muscle cell migration.
DeLisser, Helmke, Cao, Pooler, Taichman, Fehrenbach, Zaman, Cui, Mohan, Baldwin, Davis, Savani, "Loss of PECAM-1 function impairs lung alveolarization." J. Biol. Chem, 28/13:8724-8731, 2006
Ballard PI, Gonazles, LW, Godinez, RI, Godinez MH, Savani RC, McCurnin DC, Gibson LL, Yoder BA, Kerecman JD, Brubb PH, Shaul PW, "Surfactant Composition and Function in a Primate Model of Infant Chronic Lung Disease: Effects of Inhaled Nitric Oxide." Pediatric Research, 59/1:157-162, 2005
Casey, Kaplan, Atochina, Gow, Kadire, Tomer, Fisher, Hawgood, Savani, Beers., "Alveolar Surgactant Protein D Content Modulates Bleomycin Induced Lung Injury" Am. J. Respir. Crit Care Med., 172/7:869-877, 2005
Zaman A, Cui Z, Foley JP, Grimm PC, DeLisser HM, Savani RC, "Expression and role of the hyaluronan receptor RHAMM in Inflammation after bleomycin injury" Am J Respir Cell Mol Biol, 33:447-454, 2005
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