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Lydia E. MatesicAssistant Professor ofBiological Sciences
Ph.D. 2000, Johns Hopkins University
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Lydia E. MatesicAssistant Professor ofBiological Sciences
Ph.D. 2000, Johns Hopkins University
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1) Autoimmune disease: Autoimmune disease is a major health problem in the US. Collectively this group of more than 80 diseases (including Multiple Sclerosis, Lupus, Rheumatoid arthritis, and Type I Diabetes) is estimated to affect 5-8% of the US population, accounting for high health care costs and loss of productivity. Autoimmune disease is the consequence of the loss of self vs. non-self discrimination in the immune system that ultimately results in the destruction of the body's own tissues. The specificity of which tissues are targeted is characteristic of an individual autoimmune disease (e.g., type I diabetes affects just the beta-islet cells of the pancreas while lupus is systemic). The etiology of autoimmune disease has proven difficult to elucidate because both the genetic background of the individual and the environment can contribute to onset and severity. For these same reasons, effective treatments for most types of autoimmune disease are lacking. My studies aim to address this problem using a mouse mutant called itchy. Homozygous loss-of-function itch mice develop a systemic and progressive autoimmune disease, which proves fatal at 6-9 months of age due to compromised lung function. Many aspects of this phenotype are reminiscent of what is seen in human autoimmune diseases. My research uses this mouse model to identify genes and signaling pathways that are changed in itchy mice, and then translate these findings to humans to see if those same genes and pathways are similarly altered in human autoimmune disease. This model also provides a useful system for testing potential therapeutics.
2) Lung Development: In collaboration with Dr. Emery Bresnick at University of Wisconsin, Madison, we have been examining the consequence of the loss-of-function of Wwp1. We found that animals with no Wwp1 are viable and fertile with no gross or histological abnormalities. However, in combination with the loss-of-function of Itch, this mutation proved fatal within 72 hours of birth due to lung hemorrhage.
Characterization of the development of these doubly mutant embryos revealed a defect in lung development, with an arrest at the canalicular stage, as well as an overall fragility of the vasculature. There were some embryos that showed detectable hemorrhage in the ventricles of the brain, in the cardiac sac, in the meninges of the spinal column, or even in the developing lungs at E14.5. This phenotype is reminiscent of what is seen in idiopathic pulmonary hemorrhage (a common complication of preterm infants with respiratory distress) and could prove useful in understanding defects in pulmonary development and vasculogenesis. My lab is currently investigating the molecular mechanism behind this intriguing phenotype.
3) Colorectal Cancer: Collaborative research with Hans Clevers has shown that Itch is differentially expressed in the colonic epithelium with the highest expression being detected in mature cell types of the villi, while Wnt signaling is restricted to the proliferative cells of the crypts. In itchy mice, hyperproliferation of the crypts is noted with associated infiltration of eosinophils in the lamina propria of the intestines, suggesting that Itch may be important in establishing cellular differentiation and senescence by restricting Wnt signaling. As part of the Center for Colon Cancer Research at USC/MUSC, my lab is examining the role of Itch in colorectal tumorigenesis.
4) TBD: Animals lacking Wwp2 are viable and fertile with no outward signs of disease. Currently this mutation is being bred to both itch-/-and to Wwp1-/- mice to see what important biological processes are disturbed when combinations of these C2-WW-HECT E3's are not present.
Wu X. S., K. Rao, H. Zhang, F. Wang, J. R. Sellers, L. E. Matesic, N. G. Copeland, N. A. Jenkins, and J. A. Hammer III. (2002) Identification of an organelle receptor for myosin-Va. Nat Cell Biol 4: 271-278.
Matesic L. E., N. G. Copeland, and N. A. Jenkins. (2002) A genetic approach to the study of vesicle transport in the mouse. In Mechanisms of Suntanning (J. P. Ortonne and R. Ballotti, Eds.), Martin Dunitz, LTD, London.
Matesic L. E. , R. Yip, A. E. Reuss, D. A. Swing, T. N. O?Sullivan, C. F. Fletcher, N. G. Copeland, and N. A. Jenkins. (2001) Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice. Proc Natl Acad Sci U S A 98: 10238-10243.
Matesic L. E. , E. L. Niemitz, A. De Maio, and R. H. Reeves. (2000) Quantitative Trait Loci Modulate Neutrophil Infiltration in the Liver during LPS-induced Inflammation. FASEB J 14: 2247-2254.
Matesic L. E. , A. De Maio, and R. H. Reeves. (1999) Mapping LPS Response Loci in mice using Recombinant Inbred and Congenic Strains. Genomics 62: 33-41.
O'Malley J., L. E. Matesic, M.C. Zink, J. D. Strandberg, M. L. Mooney, A. De Maio, and R. H. Reeves. (1998) Comparison of Acute Endotoxin-Induced Lesions in A/J and C57BL/6J Mice. J Hered 89: 525-530.
De Maio A. , M. L. Mooney, L. E. Matesic, C. N. Paidas, and R. H. Reeves. (1998) Genetic Component in the Inflammatory Response Induced by Bacterial Lipopolysaccharide. Shock 10:319-323.
Cabin D. E., J. W. McKee-Johnson, L. E. Matesic, T. Wiltshire, E. E. Rue, A. E. Mjaavedt,Y. K. Huo, J. R. Korenberg, and R. H. Reeves. (1998) Physical and Comparative Mapping of Distal Mouse Chromosome 16. Gen Res 8: 940-950.
Cancilla M. R., J. Graves, L. E. Matesic, R. H. Reeves, K. M. Tainton, K. H. A. Choo, M. A. Resnick, V. L. Larionov, and N. Y. Kouprina. (1998) Rapid cloning of mouse DNA as yeast artificial chromosomes by transformation-associated recombination (TAR). Mamm Gen 9: 157-159.