| Dr. Kimura obtained her Ph.D. in chemistry in 1979 at Hokkaido University, Sapporo, Japan. After 3 years of postdoctoral study at Queen's University, Kingston, Ontario, she joined the National Institute of Child Health and Human Development as a visiting fellow. In 1986, she moved to the Laboratory of Molecular Carcinogenesis, NCI. Since 1996, she has been head of the Endocrinology Section, Laboratory of Metabolism. |
Role of Thyroid-Specific Enhancer-Binding Protein in Development
Our research interest is to understand the mechanisms of differentiation and maintenance of homeostasis of the thyroid and lung. Particularly, current efforts are focused on understanding the role of the thyroid-specific enhancer-binding protein (T/EBP) in transcription, physiology, and development. T/EPB is a homeodomain transcription factor that 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 in the lung. T/EBP is expressed in the thyroid, lung, and ventral forebrain during early embryogenesis, suggesting that T/EBP may play a role in genesis of these organs. A mouse lacking T/EBP expression is missing the thyroid and pituitary and has severe defects in lung and hypothalamus. The establishment of a T/ebp-null mouse line unequivocally demonstrated that T/EBP is essential during development and provides an excellent animal model to study how the lung, thyroid, pituitary, and hypothalamus are formed during development.
Based on the detailed analyses of the defects in each organ, T/EBP appears to qualify as one of the master regulatory genes involved in morphogenesis of the thyroid, lung, and pituitary, which either activates or suppresses downstream target genes, ultimately leading to organ development. Our efforts have focused on identifying genes that are regulated by T/EBP during mammalian development and that are involved in organogenesis. To this end, we have carried out PCR-based subtraction library screening and microarray analysis using lungs obtained from wild-type and T/ebp-null mouse embryos. Several genes have been characterized that are expressed under the control of T/EBP in the lung during development. Efforts are also ongoing to produce and characterize a conditional T/ebp gene knock-out mouse line using the Cre-Lox P system that deletes T/EBP only in the thyroid or lung, in order to study physiological functions of T/EBP in these organs in relation to genesis, homeostasis and diseases.
Another research project is to characterize Uteroglobin-related protein (UGRP) 1 originally identified as a T/EBP downstream target gene that is highly expressed in the epithelial cells of the trachea, bronchus and bronchioles. Preliminary results suggest that UGRP1 may play a role in lung inflammation. In order to address this question, we are in process of producing UGRP1 conditional knockout mouse that specifically deletes UGRP1 only in lung and transgenic mouse that over-expresses UGRP1 in lung epithelial cells. These mice will be subjected to experimental allergic inflammation model where the effect of loss or gain of UGRP1 on the inflammatory status will be examined.
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