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Mammalian genetics. human diseases. transgenic mice. developmental biology. obesity cancerModern mammalian molecular genetics has allowed the integration of the basic academic knowledge and principles to its genuine application in molecular medicine. Therefore. insights into fundamental developmental biological processes such as cell proliferation and differentiation are being directly translated into therapies at an ever increasing pace. Our starting point was the mouse mutant. pygmy and we identified Hmga2 as the gene responsible for the mutation and demonstrated that the gene is expressed exclusively in the mesenchyme prior to its differentiation. Therefore. modulation of Hmga2 expression impacts both mesenchymal cell proliferation and differentiation and has led to the basis of the two main projects in our laboratory. Our studies in obesity have demonstrated that the pygmy mice are intransigent to various obesity inducing stimuli. Taking advantage of the various genotypes at the Hmga2 locus under normal and obese conditions. we have identified by microarray analysis a number of genes which are expressed exclusively in the adipocyte and their expression is enhanced or repressed during obesity. Currently. we are deciphering the function and molecular pathways of these genes in adipogenesis with a focus on their potential for novel insights into the etiology and pathology of obesity. The second major project arose from our studies which demonstrated that HMGA2 is at the translocation site of a number of human mesenchymal tumors. Recently. we have shown that HMGA2 is localized to the invasive front of epithelial tumors and ectopic expression of HMGA2 will induce epithelial cells to adopt a mesenchymal phenotype and become invasive. This has led to our hypothesis that there will be a number of genes. which are normally expressed in the mesenchyme. that will be required to induce epithelial cells to become metastatic. Currently. we are identifying the downstream target genes that are activated or repressed by HMGA2 in epithelial cells. Selected PublicationsD'Armiento J, Imai K, Schiltz J, Kolesnekova N, Sternberg D, Benson K, Pardo A, Selman M, Smolarek T, Vundavalli M, Sonnet J, Szabolcs M, Chada K. (2007) Identification of the benign mesenchymal tumor gene HMGA2 in lymphangiomyomatosis. Cancer Res. 67(5):1902-9. Khor TO, Hu R, Shen G, Jeong WS, Hebbar V, Chen C, Xu C, Nair S, Reddy B, Chada K, Kong AN. (2006) Pharmacogenomics of cancer chemopreventive isothiocyanate compound sulforaphane in the intestinal polyps of ApcMin/+ mice. Biopharm Drug Dispos. 27(9):407-20. Zaidi MR, Okada Y, Chada KK. (2006) Misexpression of full-length HMGA2 induces benign mesenchymal tumors in mice. Cancer Res. 66(15):7453-9. Hu R. Khor TO. Shen G. Jeong WS. Hebbar V. Chen C. Xu C. Reddy B. Chada K. Kong AN. (2006) Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane. a natural product derived from cruciferous vegetable. Carcinogenesis. In Press. Roberts KE. Barst RJ. McElroy JJ. Widlitz A. Chada K. Knowles JA. Morse JH. (2005) Bone morphogenetic protein receptor 2 mutations in adults and children with idiopathic pulmonary arterial hypertension: association with thyroid disease. Chest. 128(6 Suppl):618S. Sato K. Ueda Y. Shimasaki M. Ozaki M. Nitta N. Chada K. Ishikawa Y. Katsuda S. (2005) Pleomorphic adenoma (benign mixed tumor) of the breast: a case report and review of the literature. Pathol Res Pract. 201(4):333-9. Akai T. Ueda Y. Sasagawa Y. Hamada T. Date T. Katsuda S. Iizuka H. Okada Y. Chada K. (2004) High mobility group I-C protein in astrocytoma and glioblastoma. Pathol Res Pract. 200(9):619-24. Brants JR. Ayoubi TA. Chada K. Marchal K. Van de Ven WJ. Petit MM. (2004) Differential regulation of the insulin-like growth factor II mRNA-binding protein genes by architectural transcription factor HMGA2. FEBS Lett. 569(1-3):277-83. Miyazawa. J. Mitoro. A. Kawashiri. S. Chada K.K.. Imai. K. (2004). Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res. 64:2024-2029. Anand. A. and Chada. K. (2000). In vivo modulation of Hmgi-c reduces obesity. Nature Genetics 24:377-380. |
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