Dept. of Surgery
Division of Transplantation

Contact Information:

Office Address: LHRB 752
Phone: 205-934-5747
Websites: School of Medicine Faculty Profile


University of North Carolina at Chapel Hill 
BA, Chemistry & Zoology, 1971

University of North Carolina at Chapel Hill 
PhD, Biochemistry, 1977

University of Louisville, KY
Microvascular Surgery, 1987

Post-Graduate Training:

NIAID, NIH, Bethesda, MD 
Staff Fellow, Laboratory of Biology of Viruses, 1977-80

Research Interests:

  • Molecular Mechanisms of Angiogenesis and Tumorigenesis
  • Molecular Mechanisms of Transplantation Biology
  • Reactive Oxygen Species in Vascular Injury and Wound Repair
  • Selective Cell Transplantation

Research Description:

Ongoing efforts over the past 30+ years have examined mechanisms regulating activation of the fibroblast growth factor (FGF) ligands and their responding high affinity receptor (FGFR)-dependent signal transduction pathways modulating cell behavior both in vitro and in vivo.  Increased expression of FGF ligands and FGFR-1 are associated with several pathophysiologic conditions, including angiogenesis, neurogenesis tumorigenesis, arthritis, atherosclerosis, diabetes, wound repair and organ transplant dysfunction.   A focus on each of these areas resulted from a passion that started  when the PI observed the ability of FGF to induce site-specific angiogenesis in vivo. Ongoing efforts imply a central role for FGF/FGFR signaling during development and the etiology of several pathophysiologic conditions.  During this time, the PI has developed system biology tools and techniques, predictive biomarkers, and identification of targets for programming cellular behavior and treatment of a number of relevant human conditions.

The biologic activity of the FGF ligands involves productive HSPG-dependent cell surface interactions with FGFRs followed by activation of their intrinsic tyrosine kinase and responding signal transduction cascades.  FGFRs contain an extracellular immunoglobulin (Ig)-like domain directing ligand binding, a transmembrane region, and an intracellular split tyrosine kinase.  Structural variants of these FGFRs are generated by alternative splicing, a common phenomenon observed in a number of situations.  The major FGFR-1 splice variants give rise to receptors with either three (FGFR-1α) or two (FGFR-1β) Ig-like domains in the extracellular region.  Human breast cancer provided the first clinical evidence for alternative splicing of FGFR-1, which correlated with malignant tumorigenesis and anchorage-independent growth in vitro.  Subsequently, human astrocytomas, pancreatic adenocarcinoma, prostate/cervical cancer, and active angiogenesis have been found to exhibit increased expression of the alternatively spliced FGFR-1β isoform.  Increased expression of FGFR-1β occurs in endothelial cells during angiogenesis and in stem cells during expression in vitro and mobilization in vivo.

During the past 4 years, we have established that ligand activation of FGFR-1α and FGFR-1β induce different, distinct signal transduction cascades that traffick to either nuclear or focal adhesion sites, respectively.  The functional consequences of targeting differential signals to defined substrates within subcellular compartments are profound and relevant to both tumor, vascular, and stem cell behavior.  For instance, cells expressing  ligand-activated FGFR-1α: (a) retain their normal phenotype; (b) are contact inhibited at high density under both anchorage-dependent and -independent conditions; (c) exhibit a more differentiated genotype; and (d) exhibit enhanced sensitivity to cytotoxic treatments (e.g., oxidative stress, chemoradiation).  In contrast, cells expressing ligand activated FGFR-1β: (a) display a transformed phenotype; (b) demonstrate loss of contact inhibition under both anchorage-dependent and -independent conditions; (c) exhibit increased migratory behavior; (d) exhibit metastatic behavior in xenografts; (e) exhibit a more undifferentiated phenotype; and (f) are resistant to cytotoxic treatments.  Consequently, alternative splicing of FGFR-1α to the β isoform and concomitant changes in ligand-dependent signaling may provide a rational strategy for manipulation of cellular behavior both in vitro and in vivo.

Modulation of FGFR-1 mRNA splicing may permit the development of novel approaches for manipulating cellular function and behavior in vitro/in vivo.  Ongoing studies in this laboratory have demonstrated that Th1- and Th2-like cytokines modulate FGFR-1 mRNA isoform switching in an opposing manner.  Cytokine-based modulation of FGFR-1 isoform expression appears consistent with isoform-specific signaling and cellular behavior during a number of physiologic/pathologic conditions, a provocative correlation that may permit the development of novel therapies for a number of conditions.  Consequently, cellular responses to a pro-inflammatory microenvironment are differentially modulated by ligand activation of FGFR-1 isoforms and should be considered in a new perspective when evaluating several pathophysiologic conditions.  The balance of pro-inflammatory Th2-like and anti-inflammatory Th1-like cytokines produced locally may determine alternative splicing of FGFR-1, which when FGF ligand activated may be critical to the resolution of inflammation and repair.  Ongoing efforts continue to focus on this FGF/FGFR-1 paradigm.


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