Our Science – Kimura Website
Shioko Kimura, Ph.D.
Our research interest is to understand the mechanisms of differentiation, function and maintenance of homeostasis of the thyroid and lung. We have been particularly interested in a homeodomain transcription factor NKX2-1, also called TTF1, TITF1 or T/EBP. NKX2-1 is expressed in the thyroid, lung, and ventral forebrain during early embryogenesis and plays a role in genesis of these organs. NKX2-1 regulates expression of thyroid and lung-specific genes, including those encoding thyroid peroxidase, thyroglobulin, TSH receptor, and the Na/I symporter in the thyroid, and surfactant proteins A, B, and C, and clara cell secretary protein (also called SCGB1A1) in the lung. All the proteins are essential for the function and homeostasis of the thyroid and lung, respectively. We have used NKX2-1 knockout mouse and thyroid-specific conditional knockout mouse with the Cre-LoxP system to study the role of NKX2-1 in the thyroid. NKX2-1-thyroid-conditional knockout mouse does not completely delete NKX2-1 in their thyroid, thus presenting a NKX2-1-thyroid-conditional hypomorphic mouse. Based on the results we obtained using these mice, we currently focus on the following research aims to understand the role of NKX2-1 in the thyroid.
Identification and characterization of thyroid stem/progenitor cells. The presence of stem/progenitor cells in the thyroid has long been suggested, however no solid data supporting this notion have been available. In order to explain a thyroid phenotype of NKX2-1-thyroid-conditional hypomorphic mouse, we hypothesized the presence of stem/progenitor cells in the thyroid. Since no thyroid stem/progenitor cell-specific surface markers are known, we use side population (SP) cells as a source for stem/progenitor cells that have ability to efflux the vital dye Hoechst 33342 due to expression of the ABCG2 transporter. Our study demonstrated that thyroid SP cells possess stem/progenitor cell-like characteristics and NKX2-1 may be involved in maintaining such population of cells. We employ various techniques in aim to demonstrate that thyroid stem/progenitor cells are indeed present within SP fraction of cells. These techniques include partial thyroidectomy, primary thyroid cell culture, and xenograft of cells to nude mice. The experiments are carried out using thyroids and/or thyroid cells obtained from wild-type as well as NKX2-1-heterozygous and thyroid-conditional hypomorphic mice. The latter two mice are to study the role of NKX2-1 that might play a role in maintenance of stem/progenitor cell populations.
Mouse model of thyroid cancer. About 1/5 of NKX2-1-thyroid-conditional hypomorphic mice developed spontaneous adenomas in their thyroids when they aged. This incomplete penetration might be due to mixed genetic backgrounds. When they were treated with genotoxic mutagen, almost all of them developed thyroid adenomas as compared to 0-8% in wild-type or NKX2-1 heterozygous mice. The results suggested the role for NKX2-1 in thyroid carcinogenesis. Factors affecting spontaneous incidence of adenomas are being analyzed using NKX2-1-thyroid-conditional hypomorphic mice in different genetic backgrounds. We are also in process of establishing a radiation-induced thyroid carcinogenesis model mouse.
Another research project is to characterize Secretoglobin (SCGB) 3A2, formerly called Uteroglobin-related protein (UGRP) 1, and its homologue SCGB3A1, formerly called UGRP2. SCGB3A2 was originally identified as a NKX2-1 downstream target in lung using NKX2-1 knockout mice. SCGB3A2 is highly expressed in the epithelial cells of the trachea, bronchus and bronchioles. SCGB3A2 exhibits anti-inflammatory function as well as growth factor activity that is responsible for fetal lung development. Our recent study demonstrated that SCGB3A2 is over-expressed in lung carcinomas, in particularly adenocarcinomas in humans. On the other hand, SCGB3A1 is a known tumor suppressor. In order to further understand the physiological roles of SCGB3A1 and SCGB3A2 in lung and/or lung diseases including lung cancer, we have produced a knockout mouse line for both genes. These knockout mice will be characterized to identify additional roles for SCGB3A1 and/or SCGB3A2 in lung. Our research further focuses on identification of SCGB3A2 and/or SCGB3A1 receptors that lead to anti-inflammatory/growth factor and tumor suppressor activity, respectively.
This page was last updated on 3/9/2013.