A delicate balance exists between life and death in ecosystems, species, individuals and even neurons. A neuron can suffer a barrage of insults, and still protective factors may allow the cell to endure. However, once a critical threshold of damage is reached, the cell cannot recover. This balance of positive and negative influences affects not only the lifespan of a single neuron but can ultimately shape the lifespan of the organism itself. In order to understand the causes of accelerated and normal neurological aging in mammals, we studied two "normal aging" control strains and two senescence-accelerated mouse strains, SAMP8/Ta (S8) and SAMP10//Ta (S10), which exhibit an early onset of age-related behavioral and neuropathological phenotypes. Hippocampal gene expression analyses revealed only a few common gene expression changes with age in all four lines. The accelerated aging lines exhibited fewer upregulated genes with age, especially S8, and throughout their life showed higher expression of repetitive viral sequences and lower levels of important transcription factors. Specifically, the S8 strain demonstrated upregulation of several inflammatory genes, which may indicate elevated oxidative stress, whereas the S10 line showed increased levels of caspase 9, suggesting a higher basal level of cell death. In an attempt to detect sequence differences present within the gene expression data, we developed a web-based tool, GeSNP, that identified several genes containing mutations in the aging accelerated strains. Importantly, the S10 strain contains a splicing mutation in the mRNA of fibroblast growth factor 1 (Fgf1) that results in a C-terminal truncation eliminating most of the heparin-binding domain. Several truncated forms of Fgfs have been previously shown to act as antagonists. In order to determine if the mutant Fgf1 interferes with the effects of other co-expressed Fgfs in a dominant negative manner, we transiently transfected Fgf2 and the S10 mutant Fgf1 into primary mouse fibroblasts. Proliferation assays showed that the mutant S10 Fgf1 can indeed interfere with the mitogenic effects of Fgf2 in vitro.
|Advisor:||Heinemann, Stephen F., Goldstein, Lawrence S.B.|
|Commitee:||Carson, Dennis A., Lipton, Stuart A., Masliah, Eliezer|
|School:||University of California, San Diego|
|School Location:||United States -- California|
|Source:||DAI-B 69/11, Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Genetics|
|Keywords:||Aging, Ccl19, FGF1, Neurodegeneration, Neurological aging, Neuronal atrophy, SAMP|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be