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Thomas Jefferson University - Andrzej Fertala, PhD
Andrzej Fertala, PhD

Orthopaedic Surgery
Thomas Jefferson University
Jefferson Medical College
Department of Orthopaedic Surgery
Professor

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Mailing Address
1015 Walnut str.
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-0113
Andrzej.Fertala@jefferson.edu
Expertise and Research Interests
My primary research activities involve the area of extracellular matrix. In particular, my studies focus on (i) identifying pathomechanisms of heritable diseases of connective tissues caused by mutations in collagen genes, (ii) technologies to produce novel collagen-like proteins for biomedical applications, and (iii) developing novel approaches to limit excessive fibrosis.
In the studies on the molecular basis of the heritable diseases caused by mutations in collagenous proteins, my studies place a main emphasis on (i) osteogenesis imperfecta caused by mutations in collagen I, (ii) spondyloepiphyseal displasias caused by mutations in collagen II, and (iii) on epidermolysis bullosa caused by mutations in collagen VII.
In addition to the studies on pathomechanisms of heritable diseases of connective tissues, my work contributed significantly to developing novel technologies for the production of human recombinant collagens for a number of biomedical applications. As animal-derived collagens and gelatin, at present widely used in biomedical and pharmaceutical fields, have the potential to transmit animal-derived diseases, the ability to produce recombinant human collagens and gelatin is very attractive. The high value and the potential applicability of recombinant human collagens are reflected by an approved patent and its licensing by Thomas Jefferson University to a commercial company. In addition to already established technologies, I continue developing new approaches to the rational engineering of collagenous proteins for biomedical applications.
In response to the need for novel therapies for fibrotic diseases, my laboratory has recently initiated studies on novel approaches to limit excessive fibrosis. These new approaches are built on my discoveries of processes that govern the formation of collagen fibrils. As this process is fundamental for the formation of fibrotic deposits, my concept is that, by inhibiting the formation of collagen fibrils, it will be possible to limit fibrosis. If experimentally confirmed, this novel concept may lead to developing novel inhibitors of fibrotic processes occurring in keloids, hypertrophic scarring, and others.
Industrial Relevance
Patents: 1. Prockop, D.J., L. Ala-Kokko, A. Fertala, A. Sieron, K.I. Kivirikko, A. Geddis, T. Pihlajaniemi, Synthesis of human procollagens and collagens in recombinant DNA systems. U.S. Patent Number 5,405,757, 1995 (Patent licensed by TJU to a biotech company; FibroGen). 2. Prockop, D.J., A. Fertala, Inhibitors of collagen assembly. U.S. Patent Number 6,472,504. 2002. 3. Fertala, A., F. Ko, Collagen or collagen-like peptide containing polymeric matrices. U.S. Patent Number 6,753,311, 2004.
Keywords
collagen; extracellular matrix; recombinant collagen; fibrosis
Publications
  • 1. Fertala, A., Westerhausen, A., Morris, G., Rooney, J. E. & Prockop, D. J. (1993). Two cysteine substitutions in procollagen I: a glycine replacement near the N-terminus of alpha 1(I) chain causes lethal osteogenesis imperfecta and a glycine replacement in the alpha 2(I) chain markedly destabilizes the triple helix. Biochem J 289 ( Pt 1), 195-199.
  • 2. Sieron, A. L., Fertala, A., Ala-Kokko, L. & Prockop, D. J. (1993). Deletion of a large domain in recombinant human procollagen II does not alter the thermal stability of the triple helix. J Biol Chem 268, 21232-21237.
  • 3. Fertala, A., Sieron, A. L., Ganguly, A., Li, S. W., Ala-Kokko, L., Anumula, K. R. & Prockop, D. J. (1994). Synthesis of recombinant human procollagen II in a stably transfected tumour cell line (HT1080). Biochem J 298 ( Pt 1), 31-37.
  • 4. Fertala, A., Sieron, A. L., Hojima, Y., Ganguly, A. & Prockop, D. J. (1994). Self-assembly into fibrils of collagen II by enzymic cleavage of recombinant procollagen II. Lag period, critical concentration, and morphology of fibrils differ from collagen I. J Biol Chem 269, 11584-11589.
  • 5. Ganguly, A., Smelt, S., Mewar, R., Fertala, A., Sieron, A. L., Overhauser, J. & Prockop, D. J. (1994). Targeted insertions of two exogenous collagen genes into both alleles of their endogenous loci in cultured human cells: the insertions are directed by relatively short fragments containing the promoters and the 5' ends of the genes. Proc Natl Acad Sci U S A 91, 7365-7369.
  • 6. Ala-Kokko, L., Yuan, C. M., Le Guellec, D., Franc, S., Fertala, A., Khillan, J. S., Sokolov, B. P. & Prockop, D. J. (1996). A 1.9-Kb 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in tissues of transgenic mice that normally express only the COL1A1 gene. Ann N Y Acad Sci 785, 202-203.
  • 7. Fertala, A., Ala-Kokko, L. & Prockop, D. J. (1996). Characterization of recombinant human collagen II with Arg519-to-Cys substitution. Ann N Y Acad Sci 785, 251-253.
  • 8. Fertala, A., Holmes, D. F., Kadler, K. E., Sieron, A. L. & Prockop, D. J. (1996). Assembly in vitro of thin and thick fibrils of collagen II from recombinant procollagen II. The monomers in the tips of thick fibrils have the opposite orientation from monomers in the growing tips of collagen I fibrils. J Biol Chem 271, 14864-14869.
  • 9. Jagodzinski, P. P., Wustner, J., Kmieciak, D., Wasik, T. J., Fertala, A., Sieron, A. L., Takahashi, M., Tsuji, T., Mimura, T., Fung, M. S., Gorny, M. K., Kloczewiak, M., Kaneko, Y. & Kozbor, D. (1996). Role of the V2, V3, and CD4-binding domains of GP120 in curdlan sulfate neutralization sensitivity of HIV-1 during infection of T lymphocytes. Virology 226, 217-227.
  • 10. Li, S. W., Sieron, A. L., Fertala, A., Hojima, Y., Arnold, W. V. & Prockop, D. J. (1996). The C-proteinase that processes procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-1. Proc Natl Acad Sci U S A 93, 5127-5130.
  • 11. Arnold, W. V., Sieron, A. L., Fertala, A., Bachinger, H. P., Mechling, D. & Prockop, D. J. (1997). A cDNA cassette system for the synthesis of recombinant procollagens. Variants of procollagen II lacking a D-period are secreted as triple-helical monomers. Matrix Biol 16, 105-116.
  • 12. Fertala, A., Ala-Kokko, L., Wiaderkiewicz, R. & Prockop, D. J. (1997). Collagen II containing a Cys substitution for arg-alpha1-519. Homotrimeric monomers containing the mutation do not assemble into fibrils but alter the self-assembly of the normal protein. J Biol Chem 272, 6457-6464.
  • 13. Zafarullah, K., Brown, E. M., Kuivaniemi, H., Tromp, G., Sieron, A. L., Fertala, A. & Prockop, D. J. (1997). Synthesis and conformational properties of a recombinant C-propeptide of human type III procollagen. Matrix Biol 16, 201-209.
  • 14. Zafarullah, K., Sieron, A. L., Fertala, A., Tromp, G., Kuivaniemi, H. & Prockop, D. J. (1997). A recombinant homotrimer of type I procollagen that lacks the central two D-periods. The thermal stability of the triple helix is decreased by 2 to 4 degrees C. Matrix Biol 16, 245-253.
  • 15. Arnold, W. V., Fertala, A., Sieron, A. L., Hattori, H., Mechling, D., Bachinger, H. P. & Prockop, D. J. (1998). Recombinant procollagen II: Deletion of D period segments identifies sequences that are required for helix stabilization and generates a temperature-sensitive N-proteinase cleavage site. J Biol Chem 273, 31822-31828.
  • 16. Prockop, D. J. & Fertala, A. (1998). The collagen fibril: the almost crystalline structure. J Struct Biol 122, 111-118.
  • 17. Prockop, D. J. & Fertala, A. (1998). Inhibition of the self-assembly of collagen I into fibrils with synthetic peptides. Demonstration that assembly is driven by specific binding sites on the monomers. J Biol Chem 273, 15598-15604.
  • 18. Adachi, E., Katsumata, O., Yamashina, S., Prockop, D. J. & Fertala, A. (1999). Collagen II containing a Cys substitution for Arg-alpha1-519. Analysis by atomic force microscopy demonstrates that mutated monomers alter the topography of the surface of collagen II fibrils. Matrix Biol 18, 189-196.
  • 19. Yuan, C. M., Ala-Kokko, L., Le Guellec, D., Franc, S., Fertala, A., Khillan, J. S., Sokolov, B. P. & Prockop, D. J. (2000). Lack of a phenotype in transgenic mice aberrantly expressing COL2A1 mRNA because of highly selective post-transcriptional down-regulation. Biochem J 345 Pt 2, 377-384.
  • 20. Fertala, A., Han, W. B. & Ko, F. K. (2001). Mapping critical sites in collagen II for rational design of gene-engineered proteins for cell-supporting materials. J Biomed Mater Res 57, 48-58.
  • 21. Fertala, A., Sieron, A. L., Adachi, E. & Jimenez, S. A. (2001). Collagen II containing a Cys substitution for Arg-alpha1-519: abnormal interactions of the mutated molecules with collagen IX. Biochemistry 40, 14422-14428.
  • 22. Li, S. W., Arita, M., Fertala, A., Bao, Y., Kopen, G. C., Langsjo, T. K., Hyttinen, M. M., Helminen, H. J. & Prockop, D. J. (2001). Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. Biochem J 355, 271-278.
  • 23. Arita, M., Li, S. W., Kopen, G., Adachi, E., Jimenez, S. A. & Fertala, A. (2002). Skeletal abnormalities and ultrastructural changes of cartilage in transgenic mice expressing a collagen II gene (COL2A1) with a Cys for Arg-alpha1-519 substitution. Osteoarthritis Cartilage 10, 808-815.
  • 24. Cabral, W. A., Fertala, A., Green, L. K., Korkko, J., Forlino, A. & Marini, J. C. (2002). Procollagen with skipping of alpha 1(I) exon 41 has lower binding affinity for alpha 1(I) C-telopeptide, impaired in vitro fibrillogenesis, and altered fibril morphology. J Biol Chem 277, 4215-4222.
  • 25. Sieron, A. L., Louneva, N. & Fertala, A. (2002). Site-specific interaction of bone morphogenetic protein 2 with procollagen II. Cytokine 18, 214-221.
  • 26. Sun, Y. L., Luo, Z. P., Fertala, A. & An, K. N. (2002). Direct quantification of the flexibility of type I collagen monomer. Biochem Biophys Res Commun 295, 382-386.
  • 27. Colombo, M., Brittingham, R. J., Klement, J. F., Majsterek, I., Birk, D. E., Uitto, J. & Fertala, A. (2003). Procollagen VII self-assembly depends on site-specific interactions and is promoted by cleavage of the NC2 domain with procollagen C-proteinase. Biochemistry 42, 11434-11442.
  • 28. Majsterek, I., McAdams, E., Adachi, E., Dhume, S. T. & Fertala, A. (2003). Prospects and limitations of the rational engineering of fibrillar collagens. Protein Sci 12, 2063-2072.
  • 29. McGinley, J. C., Heller, J. E., Fertala, A., Gaughan, J. P. & Kozin, S. H. (2003). Biochemical composition and histologic structure of the forearm interosseous membrane. J Hand Surg [Am] 28, 503-510.
  • 30. Rouan, F., Lo, C. W., Fertala, A., Wahl, M., Jost, M., Rodeck, U., Uitto, J. & Richard, G. (2003). Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro. Exp Dermatol 12, 191-197.
  • 31. Brennan, D., Hu, Y., Kljuic, A., Choi, Y., Joubeh, S., Bashkin, M., Wahl, J., Fertala, A., Pulkkinen, L., Uitto, J., Christiano, A. M., Panteleyev, A. & Mahoney, M. G. (2004). Differential structural properties and expression patterns suggest functional significance for multiple mouse desmoglein 1 isoforms. Differentiation 72, 434-449.
  • 32. Kisiel, D. G., Calvete, J. J., Katzhendler, J., Fertala, A., Lazarovici, P. & Marcinkiewicz, C. (2004). Structural determinants of the selectivity of KTS-disintegrins for the alpha1beta1 integrin. FEBS Lett 577, 478-482.
  • 33. Leitinger, B., Steplewski, A. & Fertala, A. (2004). The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2. J Mol Biol 344, 993-1003.
  • 34. Steplewski, A., Ito, H., Rucker, E., Brittingham, R. J., Alabyeva, T., Gandhi, M., Ko, F. K., Birk, D. E., Jimenez, S. A. & Fertala, A. (2004). Position of single amino acid substitutions in the collagen triple helix determines their effect on structure of collagen fibrils. J Struct Biol 148, 326-337.
  • 35. Steplewski, A., Majsterek, I., McAdams, E., Rucker, E., Brittingham, R. J., Ito, H., Hirai, K., Adachi, E., Jimenez, S. A. & Fertala, A. (2004). Thermostability gradient in the collagen triple helix reveals its multi-domain structure. J Mol Biol 338, 989-998.
  • 36. Sun, Y. L., Luo, Z. P., Fertala, A. & An, K. N. (2004). Stretching type II collagen with optical tweezers. J Biomech 37, 1665-1669.
  • 37. Brittingham, R., Colombo, M., Ito, H., Steplewski, A., Birk, D. E., Uitto, J. & Fertala, A. (2005). Single amino acid substitutions in procollagen VII affect early stages of assembly of anchoring fibrils. J Biol Chem 280, 191-198.
  • 38. Fujimoto, N., Terlizzi, J., Brittingham, R., Fertala, A., McGrath, J. A. & Uitto, J. (2005). Extracellular matrix protein 1 interacts with the domain III of fibulin-1C and 1D variants through its central tandem repeat 2. Biochem Biophys Res Commun 333, 1327-1333.
  • 39. Ito, H., Rucker, E., Steplewski, A., McAdams, E., Brittingham, R. J., Alabyeva, T. & Fertala, A. (2005). Guilty by association: some collagen II mutants alter the formation of ECM as a result of atypical interaction with fibronectin. J Mol Biol 352, 382-395.
  • 40. Steplewski, A., Brittingham, R., Jimenez, S. A. & Fertala, A. (2005). Single amino acid substitutions in the C-terminus of collagen II alter its affinity for collagen IX. Biochem Biophys Res Commun 335, 749-755.
  • 41. Wang, H., Fertala, A., Ratner, B. D., Sage, E. H. & Jiang, S. (2005). Identifying the SPARC binding sites on collagen I and procollagen I by atomic force microscopy. Anal Chem 77, 6765-6771.
  • 42. Brittingham, R., Uitto, J. & Fertala, A. (2006). High-affinity binding of the NC1 domain of collagen VII to laminin 5 and collagen IV. Biochem Biophys Res Commun 343, 692-699.
  • 43. Fujimoto, N., Terlizzi, J., Aho, S., Brittingham, R., Fertala, A., Oyama, N., McGrath, J. A. & Uitto, J. (2006). Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions. Exp Dermatol 15, 300-307.
  • 44. Ito, H., Steplewski, A., Alabyeva, T. & Fertala, A. (2006). Testing the utility of rationally engineered recombinant collagen-like proteins for applications in tissue engineering. J Biomed Mater Res A 76, 551-560.
  • 45. Cabral, W. A., Makareeva, E., Letocha, A. D., Scribanu, N., Fertala, A., Steplewski, A., Keene, D. R., Persikov, A. V., Leikin, S. & Marini, J. C. (2007). Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Hum Mutat 28, 396-405.
  • 46. Rodeck, U., Fertala, A. & Uitto, J. (2007). Anchorless keratinocyte survival: an emerging pathogenic mechanism for squamous cell carcinoma in recessive dystrophic epidermolysis bullosa. Exp Dermatol 16, 465-467.
  • 47. Steplewski, A., Hintze, V. & Fertala, A. (2007). Molecular basis of organization of collagen fibrils. J Struct Biol 157, 297-307.
  • 48. Twardowski, T., Fertala, A., Orgel, J. P. & San Antonio, J. D. (2007). Type I collagen and collagen mimetics as angiogenesis promoting superpolymers. Curr Pharm Des 13, 3608-3621.
  • 49. Chung, H. J., Steplewski, A., Chung, K. Y., Uitto, J. & Fertala, A. (2008). Collagen fibril formation. A new target to limit fibrosis. J Biol Chem 283, 25879-25886.
  • 50. Hintze, V., Steplewski, A., Ito, H., Jensen, D. A., Rodeck, U. & Fertala, A. (2008). Cells expressing partially unfolded R789C/p.R989C type II procollagen mutant associated with spondyloepiphyseal dysplasia undergo apoptosis. Hum Mutat 29, 841-851.
  • 51. Sweeney, S. M., Orgel, J. P., Fertala, A., McAuliffe, J. D., Turner, K. R., Di Lullo, G. A., Chen, S., Antipova, O., Perumal, S., Ala-Kokko, L., Forlino, A., Cabral, W. A., Barnes, A. M., Marini, J. C. & San Antonio, J. D. (2008). Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J Biol Chem 283, 21187-21197.
  • 52. Chung, H. J., Jensen, D. A., Gawron, K., Steplewski, A. & Fertala, A. (2009). R992C (p.R1192C) Substitution in Collagen II Alters the Structure of Mutant Molecules and Induces the Unfolded Protein Response. J Mol Biol.
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Individual Expertise profile of Andrzej Fertala, PhD, Copyright © Andrzej Fertala, PhD.
Last Updated by Andrzej Fertala, PhD : Thursday, October 13, 2011 5:32:01 PM



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