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ANTI-HU IMMUNO-RESPONSIVENESS IN SMALL-CELL LUNG CANCER
by Meleeneh Kazarian
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 (GENETIC, MOLECULAR, AND CELLULAR BIOLOGY) December 2010
Copyright 2010 Meleeneh Kazarian
Object Description
| Title | Anti-Hu immuno-responsivenss in small-cell lung cancer |
| Author | Kazarian, Meleeneh |
| Author email | mkazaria@usc.edu; meleeneh@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular & Cellular Biology |
| School | Keck School of Medicine |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-09-27 |
| Advisor (committee chair) | Laird-Offringa, Ite A. |
| Advisor (committee member) |
Garner, Judy Kast, W. Martin Weiner, Leslie P. |
| Abstract | Small-cell lung cancer (SCLC), which accounts for up to 15% of all lung cancers, is the most aggressive lung cancer subtype and lacks effective early detection methods. Paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/SN) is one of several rare autoimmune disorders associated with SCLC (reviewed in Chapter 1). Most patients with PEM/SN have underlying SCLC and harbor high titers of antibodies against normally neuronally expressed Hu proteins. Anti-Hu reactivity is also present in approximately 16% of SCLC patients without PEM/SN (Chapter 2). Abnormal expression of neuronal Hu proteins in SCLC tumors is thought to result in the generation of autoantibodies that may cross-react with the nervous system, possibly triggering PEM/SN. We have shown that, like human SCLC patients, engineered SCLC-prone mice misexpress Hu proteins (Chapter 3). In addition, 14% of the mice harbor above background titers of anti-Hu antibodies, similar to the situation in human SCLC patients. The mice appear to show anti-Hu reactivity prior to the clinical diagnosis of SCLC. This mouse model system mimics the anti-Hu reactivity seen in human SCLC patients, and will be a very useful model system to study the development of SCLC-associated autoimmunity, its diagnostic value, and the potential protective role of oncoantigen-directed autoantibodies.; We hypothesized that a highly immunogenic post-translational modification known as isoaspartyl conversion occurs in neuronal proteins that are frequently misexpressed in SCLC tumors. Isoaspartyl conversion occurs spontaneously in the body under physiological conditions at aspartate and asparagine amino acid residues in certain sequence contexts, usually in stressed/aging cells, and is normally repaired by the enzyme protein isoaspartyl methyltransferase (PIMT). Our studies of one neuronal member of the Hu protein family, HuD, indicate the protein is prone to this modification in vitro (Chapter 4). We have developed an isoaspartyl-specific anti-HuD antiserum, and show increased reactivity with this antiserum in the brains of PIMT knockout mice, suggesting that HuD can acquire the isoapartyl modification in vivo. We have observed that, in comparison to the nervous system where PIMT is highly expressed, the enzyme is relatively scarce in both human and murine SCLC tumors which express high levels of isoaspartyl-prone Hu proteins. We hypothesize that this leads to the accumulation of unrepaired isoaspartyl forms of HuD and other neuronal proteins and triggers an immune response. Preliminary data supports the presence of isoaspartyl moieties in SCLC and suggests a possible mechanism for the development of immuno-responsiveness in humans and mice with SCLC. If this mechanism holds true, isoaspartyl residues could provide a cancer-specific target for detection, imaging, and treatment of SCLC. |
| Keyword | anti-Hu; autoantibody; autoantigen; small-cell lung cancer; isoaspartylation; mouse model |
| 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-m3481 |
| Rights | Kazarian, Meleeneh |
| 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-Kazarian-3455 |
| Archival file | uscthesesreloadpub_Volume48/etd-Kazarian-3455.pdf |
Description
| Title | Page 1 |
| Full text | ANTI-HU IMMUNO-RESPONSIVENESS IN SMALL-CELL LUNG CANCER by Meleeneh Kazarian 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 (GENETIC, MOLECULAR, AND CELLULAR BIOLOGY) December 2010 Copyright 2010 Meleeneh Kazarian |
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