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STEM CELL AND GENE TRANSFER-BASED APPROACHES TO GENERATE INSULIN-PRODUCING CELLS by Eszter Pais 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 (SYSTEMS BIOLOGY AND DISEASE) August 2009 Copyright 2009 Eszter Pais
|Title||Stem cell and gene transfer-based approaches to generate insulin-producing cells|
|Author firstname.lastname@example.org; email@example.com|
|Degree||Doctor of Philosophy|
|Degree program||Systems Biology & Disease|
|School||Keck School of Medicine|
|Advisor (committee chair)||Lutzko, Carolyn|
|Advisor (committee member)||
Kohn, Donald B.
Meiselman, Herbert J.
Pera, Martin F.
Chow, Robert H.
|Abstract||The incidence of Diabetes Mellitus (DM) continues to increase with approximately 7.8% of the population affected in the US alone. Although pancreatic beta cell transplantation has the potential to cure the disease, limited donor tissue availability poses a major challenge. Aiming to overcome this critical shortage, we utilized two distinct, lentiviral vector-based approaches to generate or expand insulin-positive cells ex vivo.; The first set of experiments was aimed at inducing the controlled proliferation of human pancreatic beta cells through the specific activation of the Hepatocyte Growth Factor (HGF) signaling pathway in beta cells. This goal was achieved by the lentiviral delivery of a novel fusion protein (F36Vcmet) into the target cell population. Notably, this transmembrane receptor protein is active only in the presence of a synthetic ligand (AP20187). Our data provide evidence that the selective expansion of human pancreatic beta cells has been achieved utilizing this approach.; The second project described herein provides a novel tool to indicate the successful differentiation of human embryonic stem (hES) cells into the pancreatic beta cell lineage. For these purposes, we utilized an insulin promoter-driven lentiviral vector construct that specifically identifies those cultured cells that became insulin-positive. Here we show evidence that the vector designed in our laboratory is indeed specific and indicates the appearance of insulin-positive cells in the cultures reliably. As a consequence, this vector construct may be used for screening purposes to identify the optimal culture conditions that support the differentiation of hES cells into the pancreatic beta cell lineage.; Both approaches represent novel strategies aiming to increase pancreatic beta cells supply available for transplantation procedures. Although future studies and optimizations are required, if successful, these approaches have the potential to expand therapeutic options available for individuals with DM thereby improving the quality of life of millions of patients worldwide.|
|Keyword||human embryonic stem cell; diabetes; human pancreatic beta cell; lentiviral vector; differentiation|
|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|
|Legacy record ID||usctheses-m2374|
|Repository name||Libraries, University of Southern California|
|Repository address||Los Angeles, California|
|Full text||STEM CELL AND GENE TRANSFER-BASED APPROACHES TO GENERATE INSULIN-PRODUCING CELLS by Eszter Pais 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 (SYSTEMS BIOLOGY AND DISEASE) August 2009 Copyright 2009 Eszter Pais|