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Thomas Jefferson University - Mon-li H. Chu, Ph.D.
Mon-li H. Chu, Ph.D.

Dermatology and Cutaneous Biology
Thomas Jefferson University
Jefferson Medical College
Department of Dermatology & Cutaneous Biology
Professor and Vice Chair of Research

Thomas Jefferson University
Jefferson Medical College
Department of Biochemistry and Molecular Biology (secondary appointment)
Professor
Mailing Address
Thomas Jefferson University
Philadelphia, Pennsylvania 19107-6799
United States
Contact Information
Phone: (215) 503-4834
Mon-Li.Chu@jefferson.edu
Qualifications
Ph.D.,

Expertise and Research Interests
Our laboratory is engaged in elucidating the structure and function of extracellular matrix proteins and their roles in pathological conditions using a combination of molecular, biochemical, and genetic approaches. The current research activities are focused on two major areas.

The first area involves type VI collagen, which is the major component of beaded microfibrils found in almost all connective tissues. Recessive and dominant mutations in the three collagen VI genes lead to two specific types of congenital muscle disorders: the severe Ullrich congenital muscular dystrophy (UCMD) and the relatively mild Bethlem myopathy (BM). Patients afflicted with both disorders display muscle weakness accompanied by connective tissue abnormalities, including proximal joint contractures and distal joint hyperextensibility. Children with severe UCMD may never walk independently and they develop serious respiratory deficiencies, leading to death in the first and second decades of life. While BM follows a dominant inheritance the severe UCMD phenotype can result from either recessive or dominant mutations. Our laboratory is currently studying the molecular, biochemical and pathological mechanisms underlying type VI collagen gene mutations in BM and UCMD. The consequences of collagen VI mutations are investigated using fibroblasts from BM and UCMD patients. The pathophysiology of collagen VI mutations is investigated by analyzing gene targeted mouse models.

The second area involves fibulins, a family of extracellular matrix proteins that share a homologous carboxyl terminal globular domain preceded by tandem arrays of calcium-binding epidermal growth factor-like modules. The family members are found in a variety of tissues in association with diverse supramolecular structures, including elastic fibers, fibronectin microfibrils, basement membrane networks, and proteoglycan aggregates. Interestingly, most, if not all, fibulins are intimately associated with elastic fibers, and in particular, fibulin-4 and fibulin-5 play essential roles in elastic fiber assembly. Recent studies have associated defects in several fibulins with a range of human diseases, including cutis laxa, cancer, and both inherited and age-related forms of macular degeneration. However, the precise roles of most fibulins in normal and pathological conditions are still largely unknown. Our laboratory is studying the role of fibulins, with an emphasis on the elastic fiber organization, through analyses of gene-targeted mice deficient in one or more fibulins.

Keywords
Antibody Formation; Basement Membrane; Biochemistry; Cell Biology; Chimeric Protein; Collagen; Collagen Disorder; Complementary DNA; Computer Assisted Sequence Analysis; Developmental Biology; Developmental Genetics; Elastic Fiber; Extracellular Matrix Protein; Fibulin; Fluorescence Microscopy; Fusion Gene; Gel Electrophoresis; Gene Expression; Gene Mutation; Genetic Mapping; Genetic Promoter Element; Genetic Regulatory Element; Genetic Technique; Genetics; Human Genetic Material Tag; Human Physiology; Human Subject; Human Tissue; In Situ Hybridization; Laboratory Mouse; Messenger RNA; Molecular Cloning; Northern Blotting; Nucleic Acid Sequence; Pharmacology; Polymerase Chain Reaction; Protein Isoform; Protein Sequence; Protein Structure Function; Recombinant Protein; RNA Splicing; Southern Blotting; Synthetic Peptide; Tissue Cell Culture; Transcription Factor; Transfection; Transgenic Animal; Western Blotting
Publications
  • Tsuda, T., Wang, H., Timpl, R., Chu, M.-L. (2001) Fibulin-2 expression marks transformed mesenchymal cells in developing cardiac valves, aortic arch vessels, and coronary vessels. Dev. Dyn. 222, 89-100.

  • Kostka, G., Giltay, R., Bloch, W., Addicks, K., Timpl, R., Fässler, and Chu, M.-L. (2001) Perinatal lethality and endothelial cell abnormalities in several vessel compartments of fibulin-1-deficient mice. Mol. Cell. Biol. 21, 7025-7034.

  • Castoldi, M., and Chu, M.-L. (2002) Structural and Functional Characterization of the Human and Mouse Fibulin-1 Gene Promoters: Role of Sp1 and Sp3. Biochem. J. 362, 41-50.

  • Dziadek, M., Kazenwadel, J. S., Hendrey, J. A., Pan, T.-C., Zhang, R.-Z., and Chu. M.-L. (2002) Alternative splicing of transcripts for the alpha3 chain of mouse collagen VI identification of an abundant isoform lacking domains N7-N10 in mouse and human. Matrix Biol. 21, 227-241.

  • Zhang, R.Z., Sabatelli, P., Pan, T.C., Squarzoni, S., Mattioli, E., Bertini, E., Pepe, G., and Chu, M.-L. (2002). Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy. J. Biol. Chem. 277, 43557-43564.

  • Tsuda, T., Pan, T.-C., Evangelisti, L., and Chu, M.-L. (2003) Prominent expression of lysyl oxidase during mouse embryonic cardiovascular development. Anat. Rec. 270A:93-96.

  • Markova, D., Zou, Y., Ringpfeil, F., Sasaki, T., Kostka, G., Timpl, R., Uitto, U., and Chu, M.-L. (2003). Genetic heterogeneity of cutis laxa: A heterozygous tandem duplication within the fibulin-5 gene. Am. J. Hum. Genet. 72:998-1004.

  • Timpl, R., Sasaki, T., Kostka, G and Chu, M.-L. (2003) Fibulins: a versatile family of extracellular matrix proteins. Nat. Rev. Mol. Cell Biol. 4:479-489

  • Pan, T.-C., Zhang, R.-Z., Sudano, D.G., Marie, S.K., Bönnemann, C.G. and Chu, M.-L. (2003) New molecular mechanism for Ullrich congenital muscular dystrophy: A heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am. J. Hum. Genet. 73:355-369.

  • Tsuda, T., Gao, E., Evangelisti, L., Markova. D., Ma, X.L.,and Chu, M.-L. (2003) Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes. Cardiovas. Res. 59:926-993.

  • Tsuda, T., Markova1, D., Wang, H., Evangelisti, L., Pan, T.-C., and Chu, M.-L. (2004) The zinc finger protein Zac1 is expressed in chondrogenic sites of the mouse. Dev. Dyn. 229:340-348.

  • Chu, M-L., and Tsuda, T. (2004) Fibulins in development and heritable disease. Birth Defects Res Part C Embryo Today. 72:25-36.

  • Lampe, A.K., Dunn, D.M., von Niederhausern, A.C.,Hamil, C., Aoyagi, A., Laval, S.H., Chu, M.-L., Swoboda, K., Muntoni, F., Bönnemann, C.G., Flanigan, K.M., Bushby, K.M.D.; and Weiss, R.B. (2005) Automated genomic sequence analysis of the three collagen VI genes: Applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J. Med. Genet. 42:108-120.

  • Lucioli, S., Giusti, B., Mercuri, E., Camacho Vanegas, O., Lucarini, L., Pietroni, V., Urtizberea, A., Yaou, R.B., De Visser, M., Bönnemann, C., Iannaccone, S.T., Merlini, .L, Bushby, K., Muntoni, F., Bertini, E., Chu, M.-L., and Pepe, G. (2005) Detection of common and private mutations in the COL6A1 gene of Bethlem myopathy patients. Neurology, 64:1931-1937.

  • Lucarini, L, Giusti, B., Zhang, R.Z., Pan, T.C., Jimenez-Mallebrera, C., Mercuri, E., Muntoni. F., Pepe, G. Chu, M.-L. (2005) A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy. Hum Genet, 117:460-466.

  • Pepe,G., Lucarini,L., Zhang,R.Z., Pan,T.C., Giusti,B., Quijano-Roy,S., Gartioux,C., Bushby,K.M., Guicheney,P., and Chu,M.-L. (2006) COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy. Ann. Neurol., 59:190-195.

  • Kobayashi, N., Kostka, G., Garbe, J.H., Keene, D.R., Bachinger, H.P., Hanisch, F.G., Markova, D., Tsuda, T., Timpl, R., Chu, M.-L., Sasaki, T. (2007): A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization. J.Biol.Chem. 282:11805-11816.

  • Dasouki, M., Markova, D., Garola, R., Sasaki, T., Charbonneau, N.L., Sakai, L.Y. and Chu M.-L. (2007) compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly and mild cutis Laxa. Am. J. Med. Genet. A, 143:2635-2641.

  • Sicot, F-X., Tsuda, T., Markova, D., Klement, J.F., Arita, M., Zhang, R.Z., Pan, T.-C., Mecham, R.P., Birk D.E., Chu, M.-L. (2008): Fibulin-2 is Dispensable for Mouse Development and Elastic Fiber Formation. Mol.Cell Biol. 28:1061-1067.

  • Zou, Y., Zhang, R.Z., Sabatelli, P., Chu, M.-L., Bönnemann, C.G. (2008) Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle : Implications for congenital muscular dystrophy types Ullrich and Bethlem. J. Neuropath. Exp. Neurol. 67:144-154.

  • Lampe, A.K., Zou, Y., Sudano, D., O'Brien, K.K., Hicks, D., Laval, S.H., Charlton, R., Jimenez-Mallebrera, C., Zhang, R.Z., Finkel, R.S., Tennekoon, G., Schreiber, G., van der Knaap, M.S., Marks, H., Straub, V, Flanigan, K.M., Chu, M.L., Muntoni, F., Bushby, K.M., Bonnemann, C.G. (2008): Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance. Hum.Mutat. 29:809-822.

  • Williams, J.A., Kondo, N., Okabe, T., Takeshita, N., Pilchak, D.M., Koyama, E., Ochiai, T., Jensen, D., Chu, M.L., Kane, M.A., Napoli, J.L., Enomoto-Iwamoto, M., Ghyselinck, N., Chambon, P., Pacifici, M., and Iwamoto, M. (2009): Retinoic acid receptors are required for skeletal growth, matrix homeostasis and growth plate function in postnatal mouse. Dev.Biol., 328:315-327

  • Ono, R.N., Sengle, G., Charbonneau, N.L., Carlberg, V., Bachinger, H.P., Sasaki, T., Lee-Arteaga, S., Zilberberg, L., Rifkin, D.B., Ramirez, F., Chu, M.L., and Sakai, L.Y. (2009): Latent Transforming Growth Factor {beta}-binding Proteins and Fibulins Compete for Fibrillin-1 and Exhibit Exquisite Specificities in Binding Sites. J.Biol.Chem., 284:16872-16881.

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Last Updated by Mon-li Chu, Ph.D. : Thursday, July 16, 2009 2:01:36 PM


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