Research in the lab is focused on three overlapping and synergistic areas; (i) recombinant retroviruses and their use in gene therapy, (ii) cultured cells and biomaterials for tissue engineering of the skin and (iii) a combination of gene therapy and tissue engineering to produce genetically modified skin grafts to investigate the basic biology of skin and to develop new therapies for the repair of skin. 

Progress in gene therapy is hindered by the efficiency of gene transfer and we are using a quantitative approach to understand the rate limiting steps to retroviral-mediated gene transfer.  WeÕve identified proteoglycans as inhibitors of gene transfer and perfected methods for their removal as well as developed a mathematical model describing the diffusion and adsorption of active virus particles onto target cells.  We've also developed membranes and precipitation methods for the concentration and purification of biologically active retrovirus.  These studies are providing new information on the multi-step process of retroviral-mediated gene transfer and are providing the means to significantly improve the efficiency of gene transfer.

Cultured keratinocytes of the epidermis have been used to repair skin in severely burned patients, however, contrary to widespread perception, a reliable, durable and permanent skin substitute, which is functionally and cosmetically acceptable, remains a critically important, yet elusive goal.  We have had success with a composite skin substitute of cultured human keratinocytes seeded on acellular dermis.  We are also pursuing basic studies where we've used a microfabrication approach to produce an analog of the basement membrane with complex topographical features and shown that keratinocyte response varies with the dimensions of the microfabricated basement membrane, thus demonstrating that topography is an important regulator of cell function.

Using recombinant retroviruses, we've shown that cultured human keratinocytes can be genetically modified to express and secrete a variety of therapeutic proteins such as human growth hormone.  This has raised the possibility of using genetically modified skin grafts for the delivery of therapeutic proteins.  In addition to the systemic delivery of proteins, our recent work has shown that gene-modified skin grafts secreting wound healing growth factors such as PDGF and KGF can stimulate angiogenesis, as well as promote epidermal hyperproliferation.  In addition to providing basic information about the biology of the skin, this work has demonstrated that genetically modified skin grafts secreting wound healing growth factors may be useful for the repair of skin defects such as ulcers. 

Hamoen, K.E., and Morgan, J.R.  Transient Hyperproliferation of a Transgenic Human Epidermis Expressing Hepatocyte Growth Factor.  Cell Transplantation. 2002 In Press.

Erdag, G. and Morgan, J.R.  IL-1a and IL-6 Enhance the Anti-Bacterial Properties of Cultured Composite Keratinocyte Grafts.  Annals of Surgery, 2002; 235: 113-124.

Andreadis, S.T., Hamoen, K.E, Yarmush, M.L., Morgan, J.R. Keratinocyte Growth Factor Induces Hyperproliferation and Delays Differentiation of a Skin Equivalent.  FASEB J. 2001; 15: 898-906.

LeDoux, J.M., Yarmush, M.L, Morgan, J.R.  Complexation of Retrovirus with Cationic and Anionic Polymers Increases the Efficiency of Gene Transfer.  Human Gene Therapy, 2001; 12: 1611-1621.

Andreadis, S.T., Hamoen, K.E, Yarmush, M.L., Morgan, J.R. Keratinocyte Growth Factor Induces Hyperproliferation and Delays Differentiation of a Skin Equivalent.  FASEB J. 2001; 15: 898-906.

Pins, G.D., Collins-Pavao, M.E., Van De Water, L., Yarmush, M.L., Morgan, J.R.  Plasmin Triggers Rapid Contraction and Degradation of Fibroblast Populated Collagen Lattices. J. Invest. Derm. 2000; 114: 647-653.

Pins, G.D., Toner, M., Morgan, J.R.  Microfabrication of an Analog of the Basal Lamina: Biocompatible Membranes with Complex Topographies.  FASEB J. 2000; 14: 593-602.

Andreadis, S.T., Lavery, T., Davis, H.E., Le Doux, J.M., Yarmush, M.L., Morgan, J.R. Towards a More Accurate Quantitation of the Activity of Recombinant Retroviruses: Alternatives to Titer and Multiplicity of Infection.  J. Virol. 2000; 74:1258-1266.

Eming, S.A., Yarmush, M.L., Krueger, G.G., Morgan, J.R.  Regulation of the Spatial Organization of Mesenchymal Connective Tissue: Effects of Cell-Associated Versus Released Isoforms of Platelet-Derived Growth Factor.  Am. J. Path. 1999; 154: 281-289.

Medalie, D.A., Tompkins, R.G., Morgan, J.R.  Characterization of a Composite Tissue Model Which Supports Clonal Growth of Human Melanocytes In Vitro and In Vivo.   J. Invest. Derm. 1998; 111: 810-816.

Eming, S.A., Yarmush, M.L., Morgan, J.R.  Genetically Modified Keratinocytes Expressing PDGF-A   Enhance the Performance of a Composite Skin Graft.  Human Gene Therapy 1998; 9: 529-539.

Biomed Faculty Pages || Biomed || Brown University