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Genetic control of perinatal lung maturation: Lung maturation is a process critical for respiration at birth. Prematurity and accompanying lung immaturity are the most common causes of infant mortality worldwide. We are using transgenic mice, bioinformatics and in-bred mouse strains to identify the fundamental mechanisms regulating lung formation before birth (figure 1) and its growth (figure 2), differentiation (figure 3) and innate defense functions after birth.
Genetic control of airway epithelial cell function: The lung is kept sterile by complex innate and acquired immune defense systems that remove microbial pathogens and particles from the lung. The molecular mechanism controlling epithelial function in the airway is actively studied (figure 3). Genes controlling mucous production in asthma, CF and COPD have been identified and studied (figure 4). Genetic and small molecule screening are used to identify the process controlling airway epithelial cell function and to identify pathways and molecules useful for treatment of chronic lung diseases.
Progenitor / stem cells regulating lung formation and repair: We are utilizing transgenic mouse models in vivo (figure 5), and isolated lung cells in vitro, to identify the genetic programs regulating progenitor / stem cell activity of pulmonary cells. We seek to determine mechanisms controlling epithelial cell proliferation and differentiation after acute and chronic injury and during pulmonary carcinogenesis.
The respiratory epithelium is derived from the endoderm by a process of selective specification shown here in the mouse fetus compared to humans
The lung develops through five distinct stages, shown here for the mouse.
Differentiation of epithelial cells in the airway into specific subtypes with discrete functions is controlled by expression of transcription factors and proteins.
Differentiation of epithelial cells into goblet cells, which produce mucous, is controlled by the transcription factors Spdef and FoxA2.
Lineage tracing of epithelial cells can be performed using lung specific gene promoters like the SP-C, and conditional deletion of a GFP reporter transgene. These systems enable epithelial cell fate decisions to be determined. Role of Sox2, KLF-5, FoxA2 and SPDEF in lung cell fate decisions has been addressed using conditional transgenic models (see representative publications 2-5).
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