Browsing by Author "LaRocca, Thomas J., committee member"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Open Access Characterization of the Dunkin Hartley guinea pig as a non-transgenic and multimorbid model of brain aging(Colorado State University. Libraries, 2024) Glennie, Kristen Skye, author; Hamilton, Karyn L., advisor; Moreno, Julie A., advisor; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberAlzheimer's Disease and Alzheimer's Disease Related Dementia (AD/ADRD) affect an estimated 55 million people worldwide; a staggering figure that is expected to grow in the coming years. With this projection looming, we have yet to identify any effective cures, treatments, or preventative strategies. Historically, AD/ADRD research is conducted using genetically engineered pre-clinical models, that express a specific brain aging pathology. Recent discoveries, however, have identified a dynamic whole-body "inflammaging" phenotype that exists with, and likely contributes to, AD/ADRD onset and progression. Currently, we do not have an accessible and tractable preclinical model that naturally mimics the age-related, systemic and progressive neurodegenerative phenotype present in humans. Recent findings, however, suggest the Dunkin Hartley guinea pig (HGP) may address this need. HGPs are known to develop systemic inflammation and progressive age-related comorbidities characteristic of human aging. The presence of this whole-body aging phenotype prompted investigation into the brain. Genetic and transcriptomic analyses found aged HGPs exhibit strong sequence homology, and similar protein expression patterns to human brain aging and AD. Further, immunohistochemical assessment found aged HGPs express markers of neuroinflammation and misfolded proteins in the hippocampus. To further interrogate these novel findings, we examined the histopathology of 4 brain regions often implicated in neurodegenerative decline for evidence of progressive neuropathology. Our results identify the presence of an age related neuroinflammatory and phosphorylated tau phenotype. Findings from this study contribute to the overarching hypothesis that AD/ADRD is a whole-body disease, and ultimately support the goal of closing the existing translational gap between preclinical and clinical neurodegenerative research.Item Open Access Small RNA methylation in Caenorhabditis elegans(Colorado State University. Libraries, 2020) Svendsen, Joshua, author; Montgomery, Taiowa A., advisor; Wilusz, Carol J., committee member; Nishimura, Erin Osborne, committee member; LaRocca, Thomas J., committee memberEukaryotes employ small RNAs and RNA interference (RNAi) for such diverse tasks as regulating gene expression, suppressing viral infections, and defending their genomes from foreign or parasitic sequences such as pseudogenes or transposons. In the germlines of animals, piwi-interacting RNAs (piRNAs) target and silence sequences such as these to ensure that genetic information passes from one generation to the next intact. For many animals, piRNAs must be methylated at their 3' ends to protect them from degradation, and loss of stable piRNAs results in sterility. In this study, we identify a role for piRNA methylation in maintaining germline integrity in C. elegans. We also show that methylation is important for piRNA stability in worm embryos but dispensable in the adult germline. Further, we identify additional classes of methylated small RNAs: exogenous primary short interfering RNAs (siRNAs) and a subpopulation of micro RNAs (miRNAs), as well as characterizing factors that influence which small RNAs are methylated. Finally, we provide a brief review of recent advances in the field of piRNA biology that detail the rules governing piRNA targeting and a means by which endogenous C. elegans genes avoid silencing by the piRNA-dependent RNAi pathway.Item Embargo Targeting proteostatic maintenance and mitochondrial function with phytochemical compounds in models of brain and skeletal muscle aging(Colorado State University. Libraries, 2024) Walsh, Maureen Ann, author; Hamilton, Karyn L., advisor; Fling, Brett W., committee member; Moreno, Julie A., committee member; LaRocca, Thomas J., committee member; Santangelo, Kelly S., committee memberThere is a growing population of older adults (>65+ years) worldwide that is projected to increase in coming decades, presenting both a challenge and an opportunity. Specifically, age is the number one risk factor for chronic diseases like sarcopenia, the loss of muscle mass and function, and neurodegenerative diseases such as Alzheimer's Disease. The twelve hallmarks of aging are a collection of cellular changes that drive the aging process. Two highly interconnected hallmarks of aging that drive the development and progression of sarcopenia and neurodegeneration are loss of proteostasis (protein homeostasis) and mitochondrial dysfunction. While progress has been made in understanding the etiology of chronic diseases, treatments for age-related chronic diseases affecting skeletal muscle and the brain are lacking. One reason for the lack of effective treatments in humans is the absence of preclinical animal models that recapitulate human aging. However, our group previously identified the Hartley guinea pig as a novel model of brain and skeletal muscle aging. We then treated these guinea pigs with a phytochemical compound to delay the onset and/or slow the progression of brain and skeletal muscle aging. Through the experiments in this dissertation, I observed that: 1.) phytochemical compounds, branded as Protandim, can improve mechanisms of proteostasis independent of changes in mitochondrial respiration in muscle precursor cells; 2.) the phytochemical compound, branded as PB125, can improve mechanisms of skeletal muscle proteostasis in the Hartley guinea pig; 3.) PB125 can also decrease neuroinflammation in the Hartley guinea pig; and 4.) despite the lack of declines in hippocampal mitochondrial respiration with age, Hartley guinea pigs exhibit decreased mitochondrial efficiency. Collectively, this dissertation builds on prior work suggesting that the Hartley guinea pig is a valuable model to test preclinical interventions.