Browsing by Subject "Animal models"

Now showing 1 - 4 of 4
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    Effect of obesity on hepatic drug metabolism
    (2013-09) Chiney, Manoj Shriram
    Obesity has increased markedly over the last few decades and is now a major public health crisis in the U.S. affecting over 1/3 of the US population. Optimization of dosing in obese individuals is a challenge due to the lack of knowledge regarding changes in the pharmacokinetics (PK) of therapeutic agents in obese individuals. Thus the aim of this thesis was to determine the effect of obesity on drug metabolism and evaluate methods that could potentially predict changes in pharmacokinetics in the obese population. The impact of obesity on drug metabolism in children has not been determined and our clinical study (Chapter 2) was the first of its kind to examine the effect of childhood obesity on CYP1A2, CYP2D6, CYP3A4, xanthine oxidase, and NAT2 activity using caffeine and dextromethorphan as probe drugs. Our results conclusively indicate that obesity results in an elevation of xanthine oxidase and NAT2 enzyme activities in obese children as compared to lean children, whereas there was no difference in CYP1A2, CYP2D6 and CYP3A4 activity between obese and lean children. This study provides a potential mechanism of altered 6-mercaptopurine exposure in the obese pediatric cancer population. While clinical studies would provide the most optimum method to predict clearance of therapeutic agents in humans, studies have reported that clearance can also be predicted using animal data. In Chapter 3, we examined mouse, rat and porcine model of obesity in order to determine the utility of these animal models to predict PK in obese humans and to identify a model that would best reflect the human obesity mediated changes in drug metabolism. The study indicated species dependent differences in CLint of various drugs that were due to, either changes in expression of drug metabolizing enzymes or changes in enzyme substrate affinity. The study demonstrated that obesity can alter enzyme activity in a species and model dependent manner. Furthermore this study identified that the rat High Fat Diet animal model of obesity is the best representation of the obesity mediated alterations in humans. In Chapter 4, in collaboration with Drs. Scott Rector and Jim Perfield, University of Missouri, Columbia, we demonstrated obesity mediated alterations of drug metabolism enzyme activity can be prevented by sterculic oil dietary supplementation. These effects are mediated through signal transduction pathways which regulate CAR and PXR transcription factors. These results establish that obesity mediated changes are biochemically dependent and not weight dependent. In Chapter 5, we developed a proof of concept that would help generate biochemically obese hepatocytes. In absence of hepatocytes from obese individuals, these hepatocytes can be used as a tool to predict obesity mediated changes in drug clearance. Our studies indicate that individually, leptin, resistin, IL-6 and TNF-α can modulate expression of various DMEs in a concentration dependent and isoform specific manner. This study demonstrates that the obesity microenvironment is important in obesity mediated changes in drug metabolism. Additional studies would help establish a more robust method to generate and validate these obese hepatocytes. In summary, the work in this thesis has helped identify the drug metabolism enzymes that are altered in the obese children, the utility of using animal models of obesity as tools to study the impact of obesity on pharmacokinetics/pharmacodynamics, proven that it is possible to reverse obesity mediated changes in drug metabolism and developed an in vitro model that may be used to predict changes in drug disposition in the obese population. These findings are important for to better develop dosing strategies in obese humans with concomitant disease.
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    Effective Disconnection of Intrinsic Networks in the Prefrontal Cortex: Convergence across Primate and Mouse Models of Schizophrenia
    (2018-09) Zick, Jennifer
    Individuals who are afflicted with schizophrenia experience a disorienting array of symptoms that include sensations of nonexistent stimuli (hallucinations), fixed beliefs not grounded in reality (delusions), emotional disturbances, and a generalized disorganization of thought. Some of the most fundamental aspects of consciousness can be disrupted in schizophrenia, such as the capacity to maintain a continuous thought process, plan and predict future actions and consequences, discern threatening from beneficial stimuli, and consciously inhibit impulsive or harmful behavior. Descriptions of the subjective experience of schizophrenia often revolve around the idea that the executive “self” of an individual is disconnected or no longer whole. Executive functions are thought to be distributed throughout cortical and subcortical networks, but to the extent that they can be localized they tend to depend on proper functioning of regions within the prefrontal cortex. In particular, the dorsolateral prefrontal cortex (DLPFC) of primates is considered to be vital in the process of organizing thought, and likewise the disorganization of thought in schizophrenia is linked to dysfunction in this region. For example, the DLPFC contains a densely interconnected circuit of pyramidal neurons that can sustain neural activity in the absence of sensory input, which is thought to underlie our ability to maintain a concept “in mind” after it has disappeared. What happens when these fundamental processes are disrupted? The manifestations can range from subtle disturbances in the integration of sensory input to a failure to distinguish reality from imagination. In this dissertation, I describe the contributions I have made to the understanding of schizophrenia during the course of my graduate school training. I was given the opportunity to begin my work on this project by analyzing preexisting neural data obtained from the DLPFC in a pharmacological primate model of schizophrenia . From there, I developed a surgical and recording protocol that allowed me to generate comparable in vivo data from the prefrontal cortex of awake Dgcr8+/- mice, an established genetic model of schizophrenia. Despite the disparities between these two animal models, I report convergent patterns indicating a disruption of neuronal correlations in the prefrontal regions of both monkeys given dissociative drugs and mice carrying a schizophrenia-associated mutation. In both studies, I found evidence that neurons in the disease state were not synchronizing their activity with each other as effectively as in the control state. Furthermore, the effective transfer of information between pairs of neighboring neurons was reduced. These results suggest that the intrinsic circuitry of the prefrontal cortex may be disconnected in schizophrenia, and that this disconnection relates to a reduction in coincident spiking activity of neighboring neurons. It is plausible that such a dissolution of local prefrontal connectivity could result in a failure to achieve the cognitively demanding task of thought organization. While much is yet to be learned about the nature of schizophrenia, my findings have the potential to motivate the development of novel approaches to the restoration of function in this devastating disease.
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    Exploring canine trauma and hemorrhage as a translational model: epidemiology, shock index and tissue oxygen levels
    (2012-12) Wilke, Kelly
    This body of work represents initial efforts to justify the use of naturally occurring trauma in dogs as a translational model for improving trauma patient care in dogs and humans, alike (Figure 1, below). The idea for developing canine trauma as a translational model is a direct result of opportunities realized during participation in the Masters of Clinical Research program. The concept of evaluating naturally occurring diseases in dogs to enhance human patient care has become more prevalent in recent years, particularly in the fields of oncology, epilepsy and gene therapy. A canine trauma model offers an opportunity to leverage information learned from experimental canine trauma models in concert with information from spontaneous ("natural") canine models that occur in the clinical setting. The first manuscript represents a review of the veterinary and human trauma literature, drawing similarities between injury patterns in both populations and proposing the utilization of naturally occurring trauma in dogs as a model for human trauma ("Naturally occurring canine trauma: A model for early and late causes of human trauma morbidity and mortality"). Drs. Claire Sharp and Cynthia Adams contributed to the literature review and summary of articles included in the paper; generation of the manuscript involved all listed authors under the guidance and mentorship of Dr. Greg Beilman. The second manuscript ("A multi-center eight-week prospective cohort study of 315 dogs sustaining trauma") represents the initial efforts of the multicenter, multidisciplinary Spontaneous Trauma in Animals Team (STAT). The manuscript will be submitted to the Journal of the Veterinary Medical Association (JAVMA). This group first formally met in January 2011 and established a primary goal to successfully plan, obtain funding for, and perform a multi-center prospective cohort study in anticipation of performing multi-center prospective clinical trials. The STAT infrastructure is designed in anticipation of performing future intervention studies. Study execution, expertise and resources are provided by the site investigator working group [Drs. Hall (UMN), Holowaychuk (OVC), Sharp (Tufts) and Reineke (UPenn)], Data Monitoring Committee [UMN: Drs. Byrnes (MD trauma surgeon), Beilman (MD trauma surgeon), Spector (pediatric epidemiologist), Leduc (biostatistician); UPenn: Dr. Otto (veterinary criticalists, translational researcher)] and Clinical Investigation Center [UMN: Kathy Stuebner (research coordinator)], respectively. Given the successful collaborative efforts of this first research project, the group is working toward obtaining funding for pre-Phase I and Phase II trials utilizing this spontaneous model in order to efficiently evaluate therapeutic interventions (e.g., novel fluid therapies, early goal directed therapy, mesenchymal stem cell therapy) and/or non-invasive monitoring techniques to guide therapy and improve outcome (e.g., near-infrared spectroscopy, biomarkers). The group has recently expanded to add 2 additional research sites (The Ohio State University and Michigan State University) and is currently enrolling patients in a similarly designed study evaluating scoring systems and outcome in feline trauma. It is a privilege to function as the founder and lead facilitator of this collaborative working group. The third and fourth manuscripts evaluate the application of two triage tools adapted from human emergency and critical care medicine in canine patients. "Tissue oxygen saturation (StO2) in dogs presenting for acute hemorrhage" assesses the InSpectraTM Tissue Spectrometera in a population of acutely hemorrhaging dogs and "Assessment of shock index in healthy dogs and dogs in hemorrhagic shock" evaluates the utility of shock index (heart rate/systolic blood pressure) in the same population. The first project was internally funded by College of Veterinary Medicine's Small Companion Animal Grant, and co-lead by Drs. Sarah Gray and Kelly Hall (grant writing, case and data tracking, manuscript preparation). Dr. Sarah Gray presented the data at the International Veterinary Emergency and Critical Care Society conference in 2011 as part of her Emergency/Critical Care residency requirements. Drs. Schildt and Powell participated in classification of patient's shock level and manuscript creation. Dr. Ann Brearley (Biostatistical Design and Analysis Center, UMN) performed the biostatistical analysis and contributed to manuscript creation. The manuscript will be submitted to the Journal of Veterinary Emergency and Critical Care. Dr. Katie Peterson presented the shock index data in abstract form at the International Veterinary Emergency and Critical Care Society conference in 2012 as part of her Emergency/Critical Care residency requirements and took the lead on data collection and manuscript generation. Dr. Brian Hardy performed the statistical analysis and participated in manuscript generation. The Journal of Veterinary Emergency and Critical Care has accepted this article with minor revisions.
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    Remember when: the search for episodic-like memory in animals.
    (2009-09) Meyers-Manor, Julia E.
    Episodic memory refers to the rich detailed memories of events within a spatiotemporal context. It contrasts with semantic memory which includes context-free representations of facts and general knowledge. Given the frequency and severity of episodic memory deficits in humans, it would be useful to have animal models of episodic memory to better understand and treat the loss of episodic memory in humans. Some researchers have proposed that animals lack the capacity for episodic memory because of the lack of evidence for conscious self-representation in animals. However, many animal researchers have risen to the challenge and devised experiments to test various elements, features, and properties of episodic memory. The literature on episodic memory in animals is reviewed. Then three experiments examined pigeons’ memory for what events occur, where they occur, and when they occur. Two additional experiments tested the flexibility of these what-where-when memories. In Experiment 1, it was shown that pigeons had the ability to track the key location that they had to peck in order to get one of two food outcomes, which changed based on the time of day (morning or afternoon). In Experiment 2, pigeons failed to show that they could use flexibility of the what-where-when memory found in Experiment 1 in a new transfer-ofcontrol procedure. Experiment 3 and 4 examined the use of what-where-when memories in tracking food outcomes, but used how long ago events occurred rather than the time of day. The pigeons were able to use knowledge of how long ago events occurred to choose the keylight location that predicted good food rather than “rotten” or “unripe” food. Finally, in Experiment 5, the pigeons were tested on their ability to flexibly apply knowledge of “ripening” and “rotting” foods from Experiments 3 and 4 to new keylights. As in Experiment 2, the pigeons in Experiment 5 failed to show any evidence of flexibility in their what-where-when memories. Despite the results of Experiment 2 and 5, the experiments generally suggest that pigeons seem to have the basic elements required for episodic memory but may lack some of the flexibility to express those memories.