Page 1 |
Save page Remove page | Previous | 1 of 152 | Next |
|
small (250x250 max)
medium (500x500 max)
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
Subset |
HUTCHINSON GILFORD PROGERIA SYNDROME AND THE ROLE OF LAMIN
A IN THE ONSET OF THE PROGEROID CELLULAR PHENOTYPE
by
Jose Candelario
________________________________________________________________
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 MICROBIOLOGY AND IMMUNOLOGY)
May 2010
Copyright 2010 Jose Candelario
Object Description
| Title | Hutchinson Gilford progeria syndrome and the role of lamin A in the onset of the progeroid cellular phenotype |
| Author | Candelario, Jose |
| Author email | jcandela@usc.edu; jose-candelario@att.net |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Microbiology & Immunology |
| School | Keck School of Medicine |
| Date defended/completed | 2010-01-22 |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-04-01 |
| Advisor (committee chair) | Comai, Lucio |
| Advisor (committee member) |
Reddy, Sita Tahara, Stanley M. |
| Abstract | The goal of my research is to gain mechanistic insights on the molecular basis of progeria and its role to normal aging. To dissect the role of lamin A in Hutchinson Gilford Progeria Syndrome (HGPS) and the possible contribution to normal cellular aging, I created a cell model by transducing HGPS mutant lamin A (progerin) or prelamin A into normal fibroblasts. Fibroblasts expressing progerin displayed growth defects, senescence, death, nuclear membrane blebs, and irregular lamin A redistribution and aggregates recapitulating the HGPS cellular phenotype. Interestingly, fibroblats with elevated levels of prelamin A also displayed the progeria phenotype with slightly delayed kinetics. Furthermore, we observed aberrant lamin A redistribution and aggregates in cells form old aged donors suggesting a possible link between lamin A and normal aging. Growth defects and nuclear membrane blebs were rescued by farnesyl transferase inhibitor treatment or ZMPSTE24 overexpression, for cells with elevated prelamin A, suggesting the existence of one or more toxic prelamin A intermediates. Construction of prelamin A intermediates and their characterization demonstrated a cellular toxicity associated with all the variants, with the farnesylated intermediates showing the greatest toxicity. Mechanistical studies of the progeroid cellular phenotype uncovered that transcription and TBP levels are significantly reduced in cells ectopically expressing all prelamin A variants except for the mature form. To determine if alteration in gene transcription contributes to the development of the progeroid cellular phenotype we performed transcriptome analysis. Analysis of the progeroid gene expression changes allowed us to identify signaling pathways and transcription factor binding motifs that may contribute to the progeroid cellular phenotype. Furthermore, I attempted to define the first set of genes altered upon expression of progerin.; Finally, I built on these transcriptome analyses to identify genes that are successfully reverted by the treatment of FTI or ZMPSTE24. The transcription factor FOXQ1 was identified through this analysis and we showed this gene individually altered growth and nuclear morphology in normal cells. Collectively, my data provide functional insights of lamin A and its role in the progeroid cellular phenotype that suggest nuclear lamin A processing, levels, and structure are important for proper cell homeostasis. |
| Keyword | aging; Hutchinson Gilford progeria syndrome; lamin A; premature aging; progeria |
| 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-m2891 |
| Rights | Candelario, Jose |
| 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-Candelario-3584 |
| Archival file | uscthesesreloadpub_Volume23/etd-Candelario-3584.pdf |
Description
| Title | Page 1 |
| Full text | HUTCHINSON GILFORD PROGERIA SYNDROME AND THE ROLE OF LAMIN A IN THE ONSET OF THE PROGEROID CELLULAR PHENOTYPE by Jose Candelario ________________________________________________________________ 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 MICROBIOLOGY AND IMMUNOLOGY) May 2010 Copyright 2010 Jose Candelario |
Comments
Post a Comment for Page 1
