Animal Experimentation and Research Commons^™

Development Of A Pediatric Model Of Nafld In Neonatal Iberian Pigs, Gabriella Veronica Hernandez, Victoria Alice Smith, Morgan Coffin, Daniel Columbus, Matthew Burd, Kimberly Sprayberry, Mark Edwards, Daniel Peterson, Darin Bennett, Robert Fanter, Christopher Kitts, Michael La Frano, Margaret Rice, Douglas Burrin, Magdalena Maj, Rodrigo Manjarin

Master's Theses

The prevalence of non-alcoholic fatty liver disease (NAFLD) in children has increased over the past decades, creating a need for animal models that recapitulate the features of the pediatric disease. Iberian pigs have a leptin-resistant phenotype characterized by hyperleptinemia, hyperphagia, and extreme adipogenesis. We hypothesized that neonatal Iberian pigs fed a high fat high-fructose (HFF) diet will develop a pattern of liver injury resembling pediatric NAFLD. In addition, we sought to determine if a mixture of probiotics would prevent the disease. Animals were fed 1 of 4 diets containing (g/kg body weight × d) 0 g fructose, 11 g fat …

Development Of A Long-Acting Nanoformulation Of Dolutegravir For Prevention And Treatment Of Hiv-1 Infection, Brady Sillman

Theses & Dissertations

Dolutegravir (DTG) is a potent human immunodeficiency virus type 1 (HIV-1) integrase strand-transfer inhibitor (INSTI) with a high barrier to viral drug resistance. However, opportunities to improve its profile abound. These include extending the drug’s apparent half-life, increasing penetrance to “putative” viral reservoirs, and reducing inherent toxicities. These highlight, in part, the need for long-acting, slow effective release antiretroviral therapy (LASER ART) delivery schemes. A long-acting (LA) DTG was made by synthesizing a hydrophobic and lipophilic prodrug encased with poloxamer (P407) surfactant. This modified DTG (MDTG) reduced systemic metabolism and polarity, increased lipophilicity and membrane permeability, improved encapsulation, and formed …

Deicing Salts Influence Ranavirus Outbreaks In Wood Frog (Lithobates Sylvaticus) Tadpoles, Sarah Jacobson

Honors Scholar Theses

Ecosystems are increasingly being exposed to anthropogenic stressors that could make animals and thus populations more susceptible to disease. For example, the application of deicing salts to roads is increasing in the northeastern United States. Chronic stress that larval amphibians experience when living in vernal pools with high salinity may alter their susceptibility to ranavirus, a pathogen responsible for mass mortality events worldwide. This project quantifies the effects of road salts and ranavirus exposure on larval wood frog (Lithobates sylvaticus) growth and survival. Using outdoor mesocsoms, we raised wood frog tadpoles in salt treatments and then exposed them …

The Impacts Of Administering Metabolites Of Saccharomyces Cerevisiae On Broiler Performance, Yields And Salmonella Content Of Component Portions, Bill Douglas Potter

Graduate Theses and Dissertations

The impacts of using health-promoting Saccharomyces cerevisiae fermentation metabolites in poultry production and processing can be measured in respect to multiple measures of success. Traditionally this yeast-based compound has been administered to poultry, livestock, poultry, and other species to improve animal performance and production volume output. In addition, Saccharomyces cerevisiae fermentation metabolites have also been shown in more recent research to reduce colonization of pathogenic bacteria in the host organism’s gastro-intestinal tract. In this dissertation, the impacts of administering a functional ingredient containing Saccharomyces cerevisiae metabolites on broiler performance measures and pathogen reduction were measured. One of the studies in …

Welfare Challenges Influence The Complexity Of Movement: Fractal Analysis Of Behaviour In Zebrafish, Anthony G. Deakin, Joseph W. Spencer, Andrew R. Cossins, Iain S. Young, Lynne U. Sneddon

Experimental Research and Animal Welfare Collection

The ability to assess welfare is an important refinement that will ensure the good condition of animals used in experimentation. The present study investigated the impact of invasive procedures on the patterns of movement of zebrafish (Danio rerio). Recordings were made before and after fin clipping, PIT tagging and a standard pain test and these were compared with control and sham handled zebrafish. The fractal dimension (FD) from the 3D trajectories was calculated to determine the effect of these treatments on the complexity of movement patterns. While the FD of zebrafish trajectories did not differ over time in either the …

The Promises And Challenges Of Erythropoietin For Treatment Of Alzheimer's Disease, Jiahong Sun, Jan Michelle Martin, Victoria Vanderpoel, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood–brain barrier (BBB) and negative hematopoietic effects are the two …

Retrospective Review Of Anesthetic And Analgesic Regimens Used In Animal Research Proposals, Kathrin Herrmann, Paul A. Flecknell

Experimental Research and Animal Welfare Collection

Pain has a profound effect on an animal’s wellbeing. In Germany, researchers using animals have been legally required to reduce any possible pain, suffering, distress or lasting harm to an absolute minimum since 1972. To evaluate how these provisions have been implemented in practice, an assessment of refinements to experimental techniques was conducted by retrospectively reviewing 684 surgical interventions described in 506 animal research applications that were sent to the German competent authorities for approval in 2010. This paper focuses on the efficacy of proposed anesthesia and peri- and postoperative analgesia. Postoperative analgesia was not proposed for 30% of surgeries. …

The Moral Status Of Animal Research Subjects In Industry: A Stakeholder Analysis, Sarah Kenehan

Morality and Ethics of Animal Experimentation Collection

The use of non-human animals (hereinafter referred to as animals) in research and testing is a widely accepted practice in many industries. Millions of animals each year are subjected to painful procedures that include everything from physical mutilation to drug addiction. According to the United States Department of Agriculture (usda), over 820,812 animals were experimented on in the United States in 2016 (usda, 2017), though this count does not include rats, mice, or birds, and dubiously relies solely on the self-reporting of laboratories (Humane Society of the United States, 2011; Keen, 2019, Chapter 10 in this Volume). Estimates suggest that …

Beyond Plausibility Checks: A Case For Moral Doubt In Review Processes Of Animal Experimentation, Mara-Daria Cojocaru, Philipp Von Gall

Morality and Ethics of Animal Experimentation Collection

The fact that countries all over the world continue to develop new regulations for experimentation on non-human animals testament that this practice raises many doubts. Our aim in this chapter is to show that one important type of doubt should receive more attention: a particular type of moral doubt that could play a pivotal role in the ethical review of animal experiments. We assume that there are a range of emotions that indicate morally complex or problematic situations. When one or all of these emotions are experienced, we say that someone is experiencing moral doubt. To illustrate this point, we …

Human Wrongs In Animal Research: A Focus On Moral Injury And Reification, Jane Johnson, Anna Smajdor

Morality and Ethics of Animal Experimentation Collection

Using arguments derived from the work of Axel Honneth (2006), we show that animal research involves an institutionalized failure to recognize nonhuman animals that not only reifies animals but the human persons engaged in this process, diminishing the scope of their moral agency and causing moral injury. In this chapter, we begin by briefly articulating the harms to animals in research and the more conventional harms to humans that can arise as a result of animal research, before making a case for the ethical damage wrought by the failures of recognition inherent within the system of animal research. We conclude …

Wasted Money In United States Biomedical And Agricultural Animal Research, Jim Keen

Biomedicine and Animal Models in Research Collection

Biomedical and agricultural animal research uses millions of experimental animals and dozens of animal species each year by choice, precedent, or regulatory mandate in basic and applied life science research and toxicity testing of drugs, chemicals, and consumer products. Animal research is a large component of the international us$270 billion government-subsidized, biomedical industrial ecosystem (Chakma et al., 2014). In the United States (us) and presumably elsewhere, about half of these funds support animal research and testing (Institute of Medicine and National Research Council, 2012). Each year at least 115 million experimental animals (mostly mice and likely a significant underestimate) are …

The Scientific Problems With Using Non-Human Animals To Predict Human Response To Drugs And Disease, Ray Greek, Lisa A. Kramer

Pharmacology and Animal Models in Research Collection

Every year, and in countries around the world, significant time and resources are devoted to the noble cause of developing drugs to treat and cure human disease. With rare exception, drug interventions cannot reach commercialization without safety and efficacy having first been demonstrated in animal models. The intention of regulations, which require the use of animal models in such contexts, is to ensure that only safe and effective drugs end up being used by patients. Similarly, it is standard practice for researchers to employ animal models in their attempts to understand the way diseases present and progress in humans. Unfortunately, …

Modernizing Biomedical Training: Replacing Live Animal Laboratories With Human Simulation, John Pawlowski, David Feinstein, Marie L. Crandall, Shalin Gala

Biomedicine and Animal Models in Research Collection

This chapter reviews the global trend towards a modernization of biomedical education in favor of simulation-based training methods, which studies confirm improve student learning and transference of applied skills to clinical practice, reduce laboratory costs, and spare animals from harmful procedures.

Animal Research For Alzheimer Disease: Failures Of Science And Ethics, John J. Pippin, Sarah E. Cavanaugh, Francesca Pistollato

Biomedicine and Animal Models in Research Collection

This chapter addresses the epidemiology and current understanding of AD as a scientific and societal challenge, reviews the uses and results of animal research in basic science and drug development, and discusses risk factors and funding. Important follow-up topics, including current and in-development, human-relevant approaches for replacement of the failed animal research paradigm, deserve comparable treatment and hence are not addressed here. The reader is referred to the list of recommended readings at the end of the chapter for further discussion of these topics.

Behavioral Research On Captive Animals: Scientific And Ethical Concerns, Kimberley Jayne, Adam See

Morality and Ethics of Animal Experimentation Collection

The first half of this chapter focuses exclusively on animals that are used in laboratory behavioral research to model wild behavior, what is typically involved, problems associated with this practice, and how behavioral research has revealed scientific problems in the animal model. The second half of this chapter then addresses the ethical questions of whether scientific curiosity of animal behavior in general provides any justification for carrying out this research in this first place, with specific focus on non-human primates (nhps).

Ethics, Efficacy, And Decision-Making In Animal Research, Lawrence A. Hansen, Kori Ann Kosberg

Morality and Ethics of Animal Experimentation Collection

Few would disagree with the ethical contention that if cruelty to animals is not wrong, then nothing is wrong. In fact, it is not only wrong, but in most states in the us, it is a crime, a felony no less. And yet, intentionally inflicting pain and suffering upon animals, which meets Webster’s definition of cruelty, is routinely countenanced when vivisection (from the Latin vivi, to be alive, and secare, to cut) is performed under license for biomedical research. Deciding to embrace, or reject, or limit animal research demands our best ethical judgment; and it is complicated by factual disputes …

Ethical And Scientific Pitfalls Concerning Laboratory Research With Non-Human Primates, And Possible Solutions, Constança Carvalho, Augusta Gaspar, Andrew Knight, Luís Vicente

Morality and Ethics of Animal Experimentation Collection

Basic and applied laboratory research, whenever intrusive or invasive, presents substantial ethical challenges for ethical committees, be it with human beings or with non-human animals. In this paper we discuss the use of non-human primates (NHPs), mostly as animal models, in laboratory based research. We examine the two ethical frameworks that support current legislation and guidelines: deontology and utilitarianism. While human based research is regulated under deontological principles, guidelines for laboratory animal research rely on utilitarianism. We argue that the utilitarian framework is inadequate for this purpose: on the one hand, it is almost impossible to accurately predict the benefits …

Development Of A Functional Testing Platform For The Sensory Segment Of The Neuromuscular Reflex Arc, Alisha Colon

Electronic Theses and Dissertations

Investigations of human biology and disease have been hindered by the use of animal models. The information obtained from such studies often results in clinically irrelevant results and drug trial failures. Additionally, several governing bodies have been formulating legislation to move away from animal models and toward more ethical and efficient testing platforms for drug discovery and cosmetic research. As an answer to these issues, "body-on-a-chip" systems have been a rapidly developing field which easily recapitulates in vivo functionality, providing a more relevant, repeatable, and ethical testing platform to better predict biology. These systems can be used as human-based testing …

Hematologic Safety Of Chronic Brain-Penetrating Erythropoietin Dosing In App/Ps1 Mice, Jiahong Sun, Joshua Yang, Kathrine Whitman, Charlene Zhu, David H. Cribbs, Ruben J. Boado, William M. Pardridge, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Introduction: Low blood-brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor-mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB-penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb-EPO dosing, …

Optimization Of Primary Cilia Detection In Musculoskeletal Tissue, Ragen Engel

Williams Honors College, Honors Research Projects

The objective of this research project was to optimize a laboratory technique for visualizing primary cilia in musculoskeletal tissue of young swine, specifically the growth plate of long bones. This was accomplished through varying fixation procedures, antigen retrieval methods, antibody concentrations, and incubation times. By varying these parameters, a reproducible procedure was developed to examine the primary cilia in multiple tissues including ligament, fascia, and growth plate. This experiment introduced variances in fixation methods, with methanol or formalin. Paraffin and frozen embedding techniques were also varied for comparison with regards to cilia visualization. Results from the acetylated alpha tubulin (aTUB) …

Evaluating The Effects Of Antibody-Conjugated Multi-Walled Carbon Nanotubes In Combination With Microwave Irradiation, Amy Chall

College of Graduate Studies: Theses & Dissertations

Cancer remains one of the largest public health concerns of our day, particularly in developed countries where technological advances have allowed populations to live well into their eighth decade. In America, those in their 80’s have a 1 in 2 chance of developing cancer in their lifetime. Prostate cancer, specifically is the second leading cause of cancer deaths in males. Traditional cancer therapies cause high levels of toxicity to the patient due to mechanisms of action that often attack cancer cells and healthy cells alike. The holy grail of cancer research is to find a treatment that targets the cancer …

A Two Compartment Pharmacokinetic Model Describes The Intra‐Articular Delivery And Retention Of Rhprg4 Following Acl Transection In The Yucatan Mini Pig, Mark Hurtig, Iman Zaghoul, Heather Sheardown, Tannin A. Schmidt, Lina Liu, Ling Zhang, Khaled A. Elsaid, Gregory D. Jay

Pharmacy Faculty Articles and Research

Treatment of the injured joint with rhPRG4 is based on recent observations that inflammation diminishes expression of native PRG4. Re‐establishing lubrication between pressurized and sliding cartilage surfaces during locomotion promotes the nascent expression of PRG4 and thus intra‐articular (IA) treatment strategies should be supported by pharmacokinetic evidence establishing the residence time of rhPRG4. A total of 21 Yucatan minipigs weighing ∼55 Kg each received 4 mg of 131I‐rhPRG4 delivered by IA injection 5 days following surgical ACL transection. Animals were sequentially euthanized following IA rhPRG4 at 10 mins (time zero), 24, 72 hrs, 6, 13 and 20 days later. The …

No Evidence For Kin Protection In The Expression Of Sickness Behaviors In House Mice, Patricia C. Lopes, Per Block, Alice Pontiggia, Anna K. Lindholm, Barbara König

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

When infected, animals change their behaviors in several ways, including by decreasing their activity, their food and water intake, and their interest in social interactions. These behavioral alterations are collectively called sickness behaviors and, for several decades, the main hypotheses put forward to explain this phenomenon were that engaging in sickness behaviors facilitated the fever response and improved the likelihood of host survival. However, a new hypothesis was recently proposed suggesting that engaging in sickness behaviors may serve to protect kin. We tested this kin protection hypothesis by combining a field and a laboratory experiment in house mice. In both …

Development Of A Pd-L1 Pet Imaging Biomarker, Caleb Jack Bridgwater

Posters-at-the-Capitol

Immunotherapy strategies are very promising treatments for cancer patients. Specifically, Immune checkpoint inhibitor therapy focusing on the PD-1/PD-L1 pathway shows long-lasting positive results in many cancer patients. Unfortunately, not all the patients can benefit from this highly effective treatment. Hence, there is a great need for predictive biomarkers. Immunohistochemical (IHC) staining has been used as a way of predicting patient response, yet shows many problems. For example, IHC utilizes an invasive biopsy and sample fixing, which creates an incomplete and delayed picture of the patient’s biochemistry and the tumor microenvironment, consequently ignoring metastases.

The purpose of this study is to …

Diffusion Through The Ex Vivo Vitreal Body – Bovine, Porcine, And Ovine Models Are Poor Surrogates For The Human Vitreous, Sara Shafaie, Victoria Hutter, Marc B. Brown, Michael T. Cook, David Y.S. Chau

Pharmacology and Animal Models in Research Collection

The human vitreous humour is a complex gel structure whose composition and physical properties can vary considerably from person to person and also change with age. To date, the viscoelastic properties of the human vitreous gel has not been thoroughly investigated and despite many years of intensive research, an ideal vitreous substitute remains a challenge. Understanding the physical structure and properties of the vitreous is of fundamental and therapeutic interest, providing a clear insight into diffusion and transport of administered ophthalmic drug molecules into the vitreous. A number of mammalian surrogates, mainly bovine, porcine and ovine vitreous humours have been …

Brain Endothelial Erythrophagocytosis And Hemoglobin Transmigration Across Brain Endothelium: Implications For Pathogenesis Of Cerebral Microbleeds, Rudy Chang, Juan Castillo, Alexander C. Zambon, Tatiana B. Krasieva, Mark J. Fisher, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Peripheral endothelial cells are capable of erythrophagocytosis, but data on brain endothelial erythrophagocytosis are limited. We studied the relationship between brain endothelial erythrophagocytosis and cerebral microhemorrhage, the pathological substrate of MRI-demonstrable cerebral microbleeds. To demonstrate the erythrophagocytic capability of the brain endothelium, we studied the interactions between brain endothelial cells and red blood cells exposed to oxidative stress in vitro, and developed a new in vitro cerebral microbleeds model to study the subsequent passage of hemoglobin across the brain endothelial monolayer. Using multiple approaches, our results show marked brain endothelial erythrophagocytosis of red blood cells exposed to oxidative stress compared …

Uplc-Ms/Ms Analysis Of Dextromethorphan-O-Demethylation Kinetics In Rat Brain Microsomes, Barent N. Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Formation of dextrorphan (DXT) from dextromethorphan (DXM) has been widely used to assess cytochrome P450 2D (CYP2D) activity. Additionally, the kinetics of CYP2D activity have been well characterized in the liver microsomes. However, studies in brain microsomes are limited due to the lower microsomal content and abundance of CYP2D in the brain relative to the liver. In the present study, we developed a micro-scale enzymatic incubation method, coupled with a sensitive UPLC-MS/MS assay for the quantitation of the rate of DXT formation from DXM in brain microsomes. Rat brain microsomes were incubated with different concentrations of DXM for various times. …

Targeting Neuropeptides To Bone Fractures For Accelerated Healing, Nicholas A. Young, Jeffery J. Nielsen, Philip S. Low

The Summer Undergraduate Research Fellowship (SURF) Symposium

In patients over the age of 65 especially, bone fractures represent a significant disease burden. Non-invasive drug therapies are not available for bone fractures which represents a problem for this population. Vasoactive intestinal peptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), two neuromodulator peptides in the glucagon superfamily, have demonstrated positive regulation of osteoblast proliferation and activity. Using acidic oligopeptides, we have developed ligands that target to and accumulate at fracture sites. These targeting ligands can be synthesized in sequence with bone anabolic peptides to minimize off target effects and increase potency at the fracture site to create safer and …

Identifying The 5’End Of The Camta1 Genes In Zebrafish, Morgan Fronk

Undergraduate Honors Theses

Congenital heart diseases (CHDs) are a significant cause of infant death and are frequently caused by mutations in transcription factors. Camta1 (calmodulin binding transcription activator 1) is a transcription factor that has been proposed as a modulator in embryonic heart development and a possible cause of CHDs. The only other known member of its family in vertebrates is involved in activating a hypertrophy gene program in adult heart failure. Unlike camta2, camta1 is expressed in the embryonic heart during heart looping. However, few studies have been done on camta1. In zebrafish, there are two camta1 ohnologs (homologs created through …

Transcriptomics Of Learning, Pablo Iturralde

Theses

Learning is a basic and important component of behavior yet we have very little empirical information about the interaction between mechanisms of learning and evolution. In our work, we are testing hypotheses about the neurogenetic mechanisms through which animal learning abilities evolve. We are able to test this directly by using experimentally evolved populations of flies, which differ in learning ability. These populations were previously evolved within the lab by creating worlds with different patterns of change following theoretically predicted effects on which enhanced learning will evolve. How has evolution acted to modulate genes and gene expression in the brain …