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i
PTEN REGULATES BETA-CELL REGENERATION INTRINSICALLY AND
INDEPENDENTLY OF DEVELOPMENT
by
Jennifer-Ann Bayan
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
August 2012
Copyright 2012 Jennifer-Ann Bayan
Object Description
| Title | Pten regulates beta-cell regeneration intrinsically and independently of development |
| Author | Bayan, Jennifer-Ann |
| Author email | bayan@usc.edu;jennifer.bayan@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology and Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2012-06-06 |
| Date submitted | 2012-08-02 |
| Date approved | 2012-08-02 |
| Restricted until | 2012-08-02 |
| Date published | 2012-08-02 |
| Advisor (committee chair) | Stiles, Bangyan |
| Advisor (committee member) |
Maxson, Robert Okamoto, Curtis |
| Abstract | The pancreatic β-cells are responsible for producing insulin and maintaining glucose homeostasis. Loss of β-cells or their inability to compensate for insulin resistance is the major cause for type 1 and type 2 diabetes, respectively. Increasing β-cell mass or generating optimally functional islets in vitro for transplantation could potentially improve or cure type 1 diabetic conditions. Thus, efforts have been focused on improving β-cell mass by understanding and manipulating the mechanisms involved in their differentiation, proliferation and regeneration. Phosphatase and tensin homolog on chromosome 10 (PTEN) is a lipid phosphatase that antagonizes the function of the phosphatidylinositol-3-kinase (PI3K) signaling pathway. Targeted deletion of Pten in insulin producing cells led to a significant increase in total islet mass. This study suggests that β-cell regeneration may be under mitogenic regulation and that PTEN may be regulating β-cell regeneration in a paracrine fashion. Using a conditional knockout mouse model inducing the deletion of Pten, the data show that this deletion in adult and aged β-cells induced their proliferation and increased their islet mass. These mice showed enhanced metabolic function and resistance to streptozotocin (STZ)-induced diabetes. There was also evidence of G1/S protein involvement and no insulinoma development. The role of stellate cells in the growth and regeneration of pancreatic β-cells was then examined. Deletion of Pten was accompanied by an increase in activity surrounding islets treated with STZ. The cells surrounding the islets were activated mesenchymal cells displaying markers of pancreatic stellate cells. Further studies demonstrated that these activated stellate cells support the proliferation of β-cells. Therefore, the loss of PTEN specifically in the β-cells leads to a paracrine effect inducing the proliferative activity of surrounding mesencymal cells. Together, our present study suggests that the signaling regulated by PTEN plays a key role in β-cell proliferation and maintenance and β-cell regeneration may be under mitogenic regulation with PTEN regulating β-cell regeneration in a paracrine fashion. |
| Keyword | beta-cells; regeneration; diabetes; Pten; pancreatic stellate cells; extracellular matrix |
| 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 |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Bayan, Jennifer-Ann |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-BayanJenni-1114.pdf |
Description
| Title | Page 1 |
| Full text | i PTEN REGULATES BETA-CELL REGENERATION INTRINSICALLY AND INDEPENDENTLY OF DEVELOPMENT by Jennifer-Ann Bayan A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) August 2012 Copyright 2012 Jennifer-Ann Bayan |
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