Rashmin C. Savani, MBChB
Associate Professor, Dept of Pediatrics

Cell Biology and Physiology Program

Address

Rm 416F, Abramson Research Center
Children's Hosp of Philadelphia
3516 Civic Center Boulevard
Philadelphia, PA 19104-4318

Office tel.: 215 590-5507
Lab tel.: 215 590-5005
Fax: 215 590-4267
E-mail: rsavani@mail.med.upenn.edu


EDUCATION

King Edward VII School, Sheffield, England: A-Levels, 1977.

University of Sheffield Medical School, England: M.B., Ch.B. (Medicine), 1982.

RESEARCH INTERESTS

• Hyaluronan and its Receptors in Inflammation, Wound Repair and Organogenesis.

Key words: Hyaluronan, CD44, RHAMM, Inflammation, Lung, Injury, Development, Lipid Rafts, Caveolae.

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DESCRIPTION OF RESEARCH

Cell motility and proliferation are integral components of the processes that occur during inflammation, wound repair and organogenesis. Increasing evidence suggests that 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 rats and that RHAMM: HA interactions regulate macrophage motility in vitro. Administration of HA-binding peptide 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, RHAMM, ß6 integrin and TNF-alpha p55/p75 receptors. In extending this project and in collaboration with Drs. Harry Ischiropoulos and Andrew Gow, 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. In collaboration with Drs. Philip and Roberta Ballard, we are examining the role of inflammation in surfactant protein gene expression after bleomycin injury, as well as correlating our findings with tracheal aspirate, plasma and urine 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. In collaboration with Dr. Horace M. DeLisser (Pulmonary, Allergy and Critical Care Division, Dept. of Medicine, UPENN), and using anti-angiogenic strategies, we are examining the contribution of angiogenesis to the process of alveolization in newborn rats and mice.

The cell and molecular biology interests of the laboratory are the signaling mechanisms mediated by HA and its receptors within lipid rafts that regulate macrophage, endothelial and vascular smooth muscle cell migration. We have established that RHAMM is a GPI-modified protein that associates with caveolin in lipid rafts and that this interaction is critical to growth factor signals stimulating cell migration.

RECENT PUBLICATIONS

Marlene Strayer, Savani RC, Gonzales LW, Zaman A, Cui Z, Veszelovszky E, Wood E, Ho Y-S, and Ballard PL. Human Surfactant Protein B promoter in transgenic animals: Temporal, spatial and stimulus-responsive regulation. American Journal of Physiology (Lung Cell and Molecular Physiology), 282: L394-L404, 2002.

Fujimoto T, Savani RC, Watari M, Day AJ, and Strauss JF III. Induction of the hyaluronic acid-binding protein, TSG-6, in cervical smooth muscle cells by tumor necrosis factor and prostaglandin E2. Am J Pathol. 160:1495-1502, 2002.

Jian B, Xu J, Connolly J, Savani RC, Narula N, Liang B, and Levy RJ. Serotonin mechanisms in heart valve disease I: serotonin induced upregulation of TGF-ß1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 161:2111-2121, 2002.

Wang F, Daugherty B, Keise LL, Wei Z, Foley JP, Savani RC, and Koval M. Heterogeneity of claudin expression by alveolar epithelial cells. Am J Respir Cell Mol Biol. 2003. in press.

Li Y, Merrill JD, Mooney K, Song L, Wang X, Guo C-J, Savani RC, Metzger DS, Douglas SD, and Ho W-Z. Morphine enhances HIV infection of neonate immune cells. Pediatr. Res. 2003, in press.

Lab

ROTATION PROJECTS FOR 2005-2006

• Cell and Molecular Mechanisms of Lung Inflammation
• Cell and Molecular Biology of Alveolar Development
• Role of Hyaluronan and Its Receptors in Lipid Raft and Caveolar Signalling.

Lab personnel:

Zheng Cui, M.D. (Research Technician)
Joseph Foley, B.S. (Research Technician)
Jeff Finklstein (Graduate Student)
Aisha Zaman, M.S. (Laboratory Manager