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MOLECULAR AND CELLULAR CHARACTERIZATION OF
ALVEOLAR EPITHELIUM
by
Beiyun Zhou
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHAMACOLOGY AND PHARMACEUTICAL SCIENCES)
May 2008
Copyright 2008 Beiyun Zhou
Object Description
| Title | Molecular and cellular characterization of alveolar epithelium |
| Author | Zhou, Beiyun |
| Author email | bzhou@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2007-11-27 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-02-19 |
| Advisor (committee chair) | Wei-Chang Shen |
| Advisor (committee member) |
Borok, Zea Ann, David Kim, Kuang-Jin Minoo, Parvis |
| Abstract | Alveolar epithelium is comprised of two morphologically distinct cell types, type I (AT1) and type II (AT2) cells, each expressing specific differentiation-related genes (e.g., aquaporin-5 (AQP5) and surfactant protein C (SP-C)). The mechanisms involved in transcriptional regulation of these cell-specific genes were investigated in vivo and in vitro. In the first study, hypertonic induction of AQP5 was demonstrated to be transcriptionally regulated and mediated by hypoxia-inducible factor (HIF 1), indicating a novel role for HIF-1 in modulating cellular adaptive responses to osmotic stress. In the second study, GATA-6 activation of AQP5 transcription was shown to be mediated through cooperative interactions with Sp1. Increased expression of GATA-6 concurrent with upregulation of AQP5 and transition to an AT1-like phenotype in AEC primary culture suggest that temporal and spatial regulation of GATA-6 contributes to activation of AQP5 transcription through protein-protein interaction with Sp1.; In the third study, Foxp2 was shown to inhibit transcriptional activation of SP-C by Nkx2.1 by preventing interaction of Nkx2.1 with its cognate DNA binding site. However, binding of FoxP2 to its cognate site was also demonstrated by EMSA and chromatin immunoprecipitation. Together with reciprocal changes in expression of FoxP2 and Nkx2.1 concurrent with downregulation of SP-C during transition of AT2 cells to AT1-like cells, these studies indicate that repression of SP-C by FoxP2 during AEC transdifferentiation occurs both in a DNA-dependent and independent fashion. In the last study, transgenic animals were generated harboring a 4.3-kb AQP5 promoter linked to an EGFP reporter. High levels of transgene expression were detected in acinar cells of salivary gland, but only low levels were present in AT1 cells in lung, indicating that 1) AQP5 transcription is differentially regulated in salivary gland and lung, and 2) additional upstream or intronic cis-active elements are likely required for high level expression in lung. In summary, these studies suggest that temporal and spatial regulation of transcription factors and their recruitment to the proximal promoter in a particular combination may be an important mechanism mediating transcriptional regulation of cell-specific gene expression in AT1 cells. |
| Keyword | alveolar epithelium; transcriptional regulation; AT2 and AT1; GATA-6, HIF-1 and Foxp2; transgenic animals |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1023 |
| Rights | Zhou, Beiyun |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Zhou-20080219 |
| Archival file | uscthesesreloadpub_Volume44/etd-Zhou-20080219.pdf |
Description
| Title | Page 1 |
| Full text | MOLECULAR AND CELLULAR CHARACTERIZATION OF ALVEOLAR EPITHELIUM by Beiyun Zhou A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHAMACOLOGY AND PHARMACEUTICAL SCIENCES) May 2008 Copyright 2008 Beiyun Zhou |
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