Volkhard Lindner, M.D., Ph.D., a full time research scientist at the Maine Medical Center Research Institute (Center for Molecular Medicine), received his M.D. and Ph.D. degree from the University of Tuebingen, Germany. He joined MMCRI in 1995 after leaving an Assistant Professor position at the University of Washington in Seattle. He serves as a member on peer review committees for grant applications to the American Heart Association at the national and affiliate level.

Research interests

Function of the Cthrc1 Gene

The focus of our laboratory is on understanding the function of the gene Collagen Triple Helix Repeat Containing-1 (Cthrc1), which was discovered in our laboratory several years ago. This gene is only found in chordates and has interesting developmental expression patterns. It is expressed in the notochord, developing inner ear, olfactory epithelium, developing heart, cartilage and bone. Interestingly, Cthrc1 is also expressed during development in exocrine and endocrine glands such as the pancreas, salivary glands and adrenal glands. In the skin, Cthrc1 localization is restricted to sensory organelles.

During wound healing Cthrc1 is induced in activated fibroblasts, i.e. the myofibroblast. Gain-of-function studies indicate that Cthrc1 inhibits collagen deposition both in vitro and in vivo. We have shown that this inhibition is mediated by an inhibition of the transforming growth factor-beta (TGF-ß) signaling pathway. In addition, we have generated Cthrc1 deficient mice.  There is incomplete penetrance of an embryonic lethal phenotype in homozygous Cthrc1 null mice. Cardiovascular defects may be responsible for this phenotype that is being analyzed in the laboratory.

Other ongoing research in the laboratory is focused in the biochemistry of Cthrc1. The molecule has a signal peptide for secretion via the ER-Golgi pathway and yet in several cell types it remains localized in the cytoplasm. Protein interaction studies are being conducted to explore cytoplasmic protein interactions.

Aberrant expression of Cthrc1 has been reported in gene chip array analyses of human cancers. Several collaborations with clinicians at the Maine Medical Center are ongoing to explore the role of Cthrc1 in human cancers. These studies are being enabled by the availability of human tissue specimens and archived pathology specimens provided by the Tissue Bank of Maine Medical Center.

Publications

• Leclair RJ, Wang Q, Benson MA, Prudovsky I, Lindner V. Intracellular Localization of Cthrc1 Characterizes Differentiated Smooth Muscle. Arterioscler Thromb Vasc Biol 2008; 28: 1332-1338.
• LeClair RJ, Durmus T, Wang Q, Pyagay P, Terzic T and Lindner V. Cthrc1 is a Novel Inhibitor of TGF-beta Signaling and Neointimal Lesion Formation. Circ Res 2007;100:826-833.
• LeClair RJ and Lindner V. The Role of Collagen Triple Helix Repeat Containing 1 (Cthrc1) in Injured Arteries, Collagen Expression and TGF-β Signaling. Trends Cardiovasc Med 2007; 17:202-205.
• Durmus T, LeClair RJ, Park K-S, Terzic A, Yoon JK, and Lindner V. Expression Analysis of the Novel Gene Collagen Triple Helix Repeat Containing-1 (Cthrc1). Gene Expr Patterns 2006; 6: 935-940.
• Pyagay P, Heroult M, Wang Q, Lehnert W, Belden J, Liaw L, Friesel RE, Lindner V. Collagen Triple Helix Repeat Containing 1 (Cthrc1), a Novel Secreted Protein in Injured and Diseased Arteries Inhibits Collagen Expression and Promotes Cell Migration. Circ Res 2005; 96: 261-268.

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