In many organ systems, epithelia produce a vigorous ciliary flow that transports biological materials along luminal surfaces and a loss of this flow has significant implications for human health. The respiratory tract, for instance, is a ciliated epithelium where flow is used to transport a protective mucus layer and a mechanism for clearing the lung after tissue damage. As a consequence, loss of ciliary flow in the respiratory tract is a contributing factor to morbidity in chronic asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Despite their importance to human health, the cellular and molecular mechanisms that underlie the development and function of ciliated epithelia are still largely unknown. We propose to study these mechanisms using a tractable model system, the Xenopus larval skin. The larval skin is one of the earliest organs to form during embryonic development, can be easily imaged, and is extremely tractable to a genetic analysis. In addition, the larval skin contains specialized epithelia cell types that are the hallmark of ciliated epithelia, including the multi-ciliate cells specialized to produce ciliary flow, cells specialized to produce mucus, and cells specialized for acid/base transport. Using this model, the proposed experiments will address two Aims. In the first Aim, experiments are proposed to determine the mechanisms that orient ciliated cells so that beat in the same direction. This property of ciliated cells, called planar cell polarity, underlies the ability to produce long range flow that is directed along the appropriate tissue axis. These experiments will dissect the patterning cues that orient ciliated cells when they form, and the role of flow in refining ciliated cell orientation. In the second Aim, experiments are proposed to determine the mechanisms that underlie the formation of cells involved in acid/base transport. These cells are directly analogous to the intercalated cells in the kidney, which play critical roles in pH regulation. These experiments will determine the role of transcription factors in the formation of these cells, and how these cells become specialized to secrete protons or the base equivalent, carbonate. The results from the experiments outlined in these Aims will provide basic information about the formation and function of specialized cells types found in ciliated epithelia, with implications for the diagnosis and treatment of human diseases that cause defects in mucociliary transport and pH mis-regulation.
Specialized epithelia play important roles in human health by generating ciliary flow in such organs as the lung and the female reproductive tract but how the specialized cell types that make up these epithelia form during embryogenesis remains largely unknown. The proposed research will use the Xenopus larval skin as a model system to determine the developmental mechanisms that underlie the formation of two specialized epithelial cell types, namely cells that are multi-ciliated and produce fluid flow and cells that mediate acid/base transport. A better understanding of these cell types will aid in the diagnosis and treatment of human disease that affect ciliated epithelia, such as the mucus clearance defects that occurs during chronic asthma, cystic fibrosis, and chronic obstructive pulmonary disease.
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