Mon-Li H. Chu, PhD
233 South Tenth Street
Philadelphia, PA 19107
Research and Clinical 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.
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
Most Recent Peer-Reviewed Publications
- Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa
- Fibulin-2 is essential for angiotensin II-induced myocardial fibrosis mediated by transforming growth factor (TGF)-β
- Forelimb contractures and abnormal tendon collagen fibrillogenesis in fibulin-4 null mice
- Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking
- Fibulin-4 E57K knock-in mice recapitulate cutaneous, vascular and skeletal defects of recessive cutis laxa 1B with both elastic fiber and collagen fibril abnormalities
- A mouse model for dominant collagen VI disorders Heterozygous Deletion of Col6a3 EXON 16
- Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy
- Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling
- Reduced fibulin-2 contributes to loss of basement membrane integrity and skin blistering in mice lacking integrin α3β1 in the epidermis
- Fibulin-2 is involved in early extracellular matrix development of the outgrowing mouse mammary epithelium.
- Clinical Significance of Serum COL6A3 in Pancreatic Ductal Adenocarcinoma
- COL6A3 protein deficiency in mice leads to muscle and tendon defects similar to human collagen VI congenital muscular dystrophy
- Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction
- Tumor-specific expression and alternative splicing of the COL6A3 gene in pancreatic cancer
- Dysfunctional tendon collagen fibrillogenesis in collagen VI null mice
- Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: Role of the C2a splice variant
- Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury
- Latent transforming growth factor β-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites
- Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance
- Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle: Implications for congenital muscular dystrophy types Ullrich and Bethlem