Research Methods in Life Sciences Commons^™

Acute And Chronic Dosing Of A High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody In Mice, Demi M. Castellanos, Jiahong Sun, Joshua Yang, Weijun Ou, Alexander C. Zambon, William M. Pardridge, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent …

Mitochondrial Contributions To Disuse Atrophy: Let’S Talk About Sex, Megan Rosa-Caldwell

Graduate Theses and Dissertations

Skeletal muscle atrophy is a hallmark of many pathologies and is associated with disease prognosis, quality of life, and mortality. Specifically, lack of contractile activity of the muscle can result in disuse-associated atrophy. Disuse-induced atrophy is a common phenomenon in intensive care unit (ICU) patients and significantly impacts patient prognosis and ability to transition of out of intensive care. However, effective therapeutics to mitigate disuse-associated atrophy do not exist, clearly demonstrating the scientific and clinical need to further understand mechanisms contributing to disuse atrophy. In particular, a significant portion of the scientific literature has utilized male models, yet there is …

Targeting The Transferrin Receptor To Develop Erythropoietin For Alzheimer’S Disease, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

"Alzheimer’s disease (AD) is the sixth leading cause of death in the United States with approximately 5.8 million Americans currently living with AD. Due to the lack of a disease modifying treatment for AD and the aging baby boomer generation, this number is projected to grow to 13.8 million by 2050 (Gaugler et al., 2019). Amyloid-beta (Aβ) plaque accumulation, one of the major pathological hallmarks of AD, can begin > 20 years before clinical symptoms of AD. By the time AD is clinically diagnosed, neuronal loss and neuropathological lesions (Aβ plaques and tau tangles) have already occurred in many brain regions …

Proteomic Identification Reveals The Role Of Ciliary Extracellular‐Like Vesicle In Cardiovascular Function, Ashraf M. Mohieldin, Rajasekharreddy Pala, Rinzhin T. Sherpa, Madhawi Alanazi, Ashwaq Alanazi, Kiumars Shamloo, Amir Ahsan, Wissam A. Aboualaiwi, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are shown to have membrane swelling, also known as ciliary bulbs. However, the role of these structures and their physiological relevance remains unknown. Here, it is reported that a ciliary bulb has extracellular vesicle (EV)‐like characteristics. The ciliary extracellular‐like vesicle (cELV) has a unique dynamic movement and can be released by mechanical fluid force. To better identify the cELV, differential multidimensional proteomic analyses are performed on the cELV. A database of 172 cELV proteins is generated, and all that examined are confirmed to be in the cELV. Repressing the expression of these proteins in vitro and in vivo …

Ctrp3 And Alcoholic Liver Disease In Female Mice, Callie Root

Undergraduate Honors Theses

C1q TNF Related Protein 3 (CTRP3), is a cytokine that is primarily secreted from adipose tissue, which classifies it as an adipokine. Our previous research has shown that CTRP3 prevents alcoholic fatty liver disease (ALD) in male mice. However, even when accounting for confounding factors such as absolute and relative alcohol intake, females are more sensitive to the effects of consumption compared to male mice. Therefore, the goal of this project was to determine whether CTRP3 prevented ALD in female mice. Methods: Female wild type (WT) and female CTRP3 transgenic over expressing (Tg) mice were fed an ethanol containing liquid …

Heterogeneous Nuclear Ribonucleoprotein K (Hnrnp K) Overexpression And Its Interaction With Runx1 Rna In Acute Myeloid Leukemia, Marisa Aitken

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is an often devastating hematologic malignancy with 5-year overall survival lingering near 20%. Acquiring a deeper understanding of molecular underpinnings of leukemogenesis will provide a basis for developing more effective therapeutic strategies for patients with AML.

Here, we identified overexpression of hnRNP K as a recurrent abnormality in a subset (~20%) of AML patients. High levels of this RNA-binding protein associated with inferior clinical outcomes in de novo AML. Thus, to evaluate its putative oncogenic capacity in myeloid disease, we overexpressed hnRNP K in murine hematopoietic stem and progenitor cells isolated from fetal liver cells (FLCs). …

Evaluation Of Anthelmintic Therapies In A Fall Calving Beef Cowherd, Laine Zammit

Graduate Theses and Dissertations

Internal parasitism inevitability prompts economic loss in beef cattle production by decreasing growth performance and reproductive traits. Today, the most widely used class of anthelmintic used to treat parasitism, is the macrocyclic lactone. Many studies have conflicting results on the efficacy of macrocyclic lactones (ML) efficacy against internal parasitism. The objective of this study was to evaluate the effectiveness of moxidectin and eprinomectin, two of the MLs, on cow performance. Multiparous fall calving, crossbred beef cows (n = 106) were allocated randomly to 1 of 3 anthelmintic treatments: 1) Negative control (CON), in which cows did not receive an anthelmintic, …

Cd44 Receptor Mediates Urate Crystal Phagocytosis By Macrophages And Regulates Inflammation In A Murine Peritoneal Model Of Acute Gout, Emira Bousoik, Marwa Qadri, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Gout is a chronic arthritis caused by the deposition of poorly soluble monosodium urate monohydrate (MSU) crystals in peripheral joints. Resident macrophages initiate inflammation in response to MSU mediated by NF-κB nuclear translocation and NLRP3 inflammasome activation. We investigated the role of CD44, a transmembrane receptor, in mediating MSU phagocytosis by macrophages. We used an antibody that sheds the extracellular domain (ECD) of CD44 to study the role of the receptor and its associated protein phosphatase 2A (PP2A) in macrophage activation. We also studied the significance of CD44 in mediating MSU inflammation in-vivo. Cd44^−/− BMDMs showed reduced MSU …

Two (Or More) Viruses In One Bat: A Systematic Quantitative Literature Review Of Viral Coinfection In Bats, Eli J. Kaufman

Independent Study Project (ISP) Collection

Viral coinfection is an important topic in pathogen dynamics, and can increase viral shedding and change disease outcomes. As bats are carriers of important zoonoses, such as the SARS coronaviruses, rabies, and other deadly viruses, knowing more about their coinfection dynamics is important. This quantitative systematic literature review sought to show how many papers reported bat viral coinfections, and created three databases. The first database, the SQLR database was based on searches for coinfections. The second database, the Astrovirus database was to determine how much of the literature was being missed by examining a single viral family more in depth …

A Neural Mechanism For Capnotaxis In The Naked Mole-Rat, Michael Zions

Dissertations, Theses, and Capstone Projects

A Neural Mechanism for Capnotaxis in the Naked Mole-Rat

The Naked Mole-Rat (NM-R) is a small hairless rodent that has thrived underground in the Horn of Africa for the past 40 million years. It was first discovered in 1847, but has only been maintained in captivity and studied as a laboratory animal over the past 40 years. To date, more than 400 scientific papers have been published on this species. This is relatively few compared to established lab animals like rats and mice, but those papers contain a trove of information that has changed our understanding of the constraints of …

Genetic And Cellular Models For The Study Of Ptk2b And Adam10 In Adaptive Thermogenesis And Metabolism, Jared S. Farrar

Theses and Dissertations

In a cellular model, we demonstrate that the non-receptor protein tyrosine kinase 2 beta (PTK2B) plays a critical role in mouse cultured beige adipocyte differentiation. CRISPR/Cas9-mediated knock-out of Ptk2b results in non-differentiating white adipocytes and differentiated beige adipocytes with significantly reduced thermogenic gene and protein expression, enlarged lipid droplet size, and altered mitochondrial respiration. Together, these data in a cell culture system provide evidence for a role of PTK2B in the differentiation of mouse beige adipocytes.

In the process of developing a new mouse model utilizing the adipocyte selective Adipoq-Cre transgenic mouse, strong genetic linkage between a gene …

Investigating The Morphology Of Iprgcs In Control Vs. Glaucomatous Retinas, Samantha Cook

Williams Honors College, Honors Research Projects

Glaucoma is a build-up of pressure in the eye that leads to the gradual loss of sight. The intention of this study was to investigate how glaucoma affects intrinsically photosensitive Retinal Ganglion Cells (ipRGCs). These cells contain melanopsin, a photopigment, that enables the cells to react to light. Four-month-old control and five-month-old glaucoma mice retinas were dissected, stained using primary and secondary antibodies, then traced using ImageJ’s Simple Neurite Tracer. There were no significant differences in soma size, total dendritic length, dendritic field size, and dendritic field diameter between control and glaucoma ipRGCs. However, further research is needed to provide …

Estimation Of Genetic Components Related To Infectious Bovine Keratoconjunctivitis Susceptibility In Angus And Angus Derived Cattle Produced In The Southern United States, Eric Oxford

Graduate Theses and Dissertations

The economic impact of infectious bovine keratoconjunctivitis (IBK) has been documented in many parts of the world. Many researchers have observed that prevention of this disease is very difficult given current methodologies. This is primarily due to the multifactorial nature of this disease. The objective of this dissertation was to determine the impact of IBK on calf performance and estimate genetic parameters, heritability and estimated breeding values for IBK susceptibility. Data were analyzed using PROC GLIMMIX of SAS; while genetic parameters were estimated using a linear animal model for both single- and two-traits through MTDFREML. Additional evaluations calculated heritability using …

Effects Of Dabigatran In Mouse Models Of Aging And Cerebral Amyloid Angiopathy, Neethu Michael, Mher Mahoney Grigoryan, Kelley Kilday, Rachita K. Sumbria, Vitaly Vasilevko, Joanne Van Ryn, David H. Cribbs, Annlia Paganini-Hill, Mark J. Fisher

Pharmacy Faculty Articles and Research

Oral anticoagulants are a critical component of stroke prevention, but carry a risk of brain hemorrhage. These hemorrhagic complications tend to occur in elderly individuals, especially those with predisposing conditions such as cerebral amyloid angiopathy (CAA). Clinical evidence suggests that non-vitamin K antagonist oral anticoagulants are safer than traditional oral anticoagulants. We analyzed whether the anticoagulant dabigatran produces cerebral microhemorrhage (the pathological substrate of MRI-demonstrable cerebral microbleeds) or intracerebral hemorrhage in aged mice with and without hemorrhage-predisposing angiopathy. We studied aged (22 months old) Tg2576 (a model of CAA) and wild-type (WT) littermate mice. Mice received either dabigatran etexilate (DE) …

Short Amylin Receptor Antagonist Peptides Improve Memory Deficits In Alzheimer’S Disease Mouse Model, Rania Soudy, Ryoichi Kimura, Aarti Patel, Wen Fu, Kamaljit Kaur, David Westaway, Jing Yang, Jack Jhamandas

Pharmacy Faculty Articles and Research

Recent evidence supports involvement of amylin and the amylin receptor in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that amylin receptor antagonist, AC253, improves spatial memory in AD mouse models. Herein, we generated and screened a peptide library and identified two short sequence amylin peptides (12–14 aa) that are proteolytically stable, brain penetrant when administered intraperitoneally, neuroprotective against Aβ toxicity and restore diminished levels of hippocampal long term potentiation in AD mice. Systemic administration of the peptides for five weeks in aged 5XFAD mice improved spatial memory, reduced amyloid plaque burden, and neuroinflammation. The common residue SQELHRLQTY …

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 …

2018 Guide Summer Research - Breast Cancer, Qur'annah Jones, Delawnia Comer-Hagans

Research Days

This research poster details the relationship between cancer treatments and alternative approaches, such as mindfulness. The purpose of this study was to determine the methodology used by doctors to treat breast cancer and their willingness to try a holistic approach. This study was conducted on site at the UIC Cancer Center as well as remotely within hospitals around the Chicagoland area. We determined that mindfulness is in fact a worthwhile asset to breast cancer patients and that the field of oncology could support further research.

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 …

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, …

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 …

Green Tea Polyphenol Epigallocatechin-3-Gallate-Stearate Inhibits The Growth Of Streptococcus Mutans: A Promising New Approach In Caries Prevention, Amy Lynn Melok, Lee Lee, Siti Ayuni Mohamed Yussof, Tinchun Chu

Department of Biology Faculty Scholarship and Creative Works

Streptococcus mutans (S. mutans) is the main etiological bacteria present in the oral cavity that leads to dental caries. All of the S. mutans in the oral cavity form biofilms that adhere to the surfaces of teeth. Dental caries are infections facilitated by the development of biofilm. An esterified derivative of epigallocatechin-3-gallate (EGCG), epigallocatechin-3-gallate-stearate (EGCG-S), was used in this study to assess its ability to inhibit the growth and biofilm formation of S. mutans. The effect of EGCG-S on bacterial growth was evaluated with colony forming units (CFU) and log reduction; biofilm formation was qualitatively determined by Congo red assay, …

Aging Exacerbates Development Of Cerebral Microbleeds In A Mouse Model, Rachita K. Sumbria, Mher Mahoney Grigoryan, Vitaly Vasilevko, Annlia Paganini-Hill, Kelley Kilday, Ronald Kim, David H. Cribbs, Mark J. Fisher

Pharmacy Faculty Articles and Research

Background: Cerebral microhemorrhages (CMH) are commonly found in the aging brain. CMH are also the neuropathological substrate of cerebral microbleeds (CMB), demonstrated on brain MRI. Recent studies demonstrate the importance of systemic inflammation in CMH development, but the relationships among inflammation, aging, and CMH development are not well-defined. In the current study, we hypothesized that the pathogenesis of inflammation-induced CMH in mice differs by age.

Methods: We studied young (3 months, n = 20) and old (18 months, n = 25) C57BL/6 mice injected with low-dose lipopolysaccharide (LPS; 1 mg/kg, i.p.) or saline at 0, 6, and 24 …

Studies Of Amino Acid Mutations In Drug Resistance Of The Smo Protein, Eunice Wintona

UNO Student Research and Creative Activity Fair

Smoothened receptor (SMO) is a protein that in humans, is encoded by the SMO gene. A systemic mutation in its binding pocket helps predict the sensitivity of mutant proteins to different drugs. Known as a GPCR-like receptor, it is a component of the hedgehog signaling pathway; a pathway involved in body patterning and the regulation of adult stem cells. An uncontrolled or inappropriate activation of the Hedgehog pathway drives tumor progression in cancers and a number of birth defects. To achieve these goals, the molecular modeling software MOE was used to build small molecules and drug molecules like Vismodegib and …

Possible Breakdown Of Dopamine Receptor Synergism In A Mouse Model Of Huntington's Disease, Samantha F. Kennedy

LSU New Orleans Theses and Dissertations

The model of basal ganglia function proposed by Albin, Young and Penney (1989) describes two anatomically independent motor pathways, the direct and indirect. However, under normal conditions striatal dopamine (DA) is required for the expression of motor behavior, and DAergic control of the two pathways (via D1 and D2 receptors, respectively) is dependent on co-activation. We tested for a possible breakdown of D1/D2 synergism using transgenic R6/1 mice bearing the human huntingtin allele (Htt). Motor stereotypy, observed prior to the onset of HD-related symptoms, was rated on a 5-point scale following activation of: A) D1 receptors alone, B) D2 receptors …

Structural Insights Into The Potency Of Sk Channel Positive Modulators, Young-Woo Nam, Razan Orfali, Tingting Liu, Kunqian Yu, Meng Cui, Heike Wulff, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca2+-activated K+ (SK) channels play essential roles in the regulation of cellular excitability and have been implicated in neurological and cardiovascular diseases through both animal model studies and human genetic association studies. Over the past two decades, positive modulators of SK channels such as NS309 and 1-EBIO have been developed. Our previous structural studies have identified the binding pocket of 1-EBIO and NS309 that is located at the interface between the channel and calmodulin. In this study, we took advantage of four compounds with potencies varying over three orders of magnitude, including 1-EBIO, NS309, SKS-11 (6-bromo-5-methyl-1H-indole-2,3-dione-3-oxime) and …

Rehabilitation Of An Injured Golden Eagle (Aquila Chrysaetos): A Case Study, Fida Muhammad Khan, Fakhar-I- Abbas, Abu Ul Hassan Faiz

Journal of Bioresource Management

Habitat destruction and anthropogenic activities cause wild birds to migrate towards urban areas in search of food and sometimes nesting in high-roof buildings, where they are caught by local people using different techniques and are further used for hunting or recreational purposes. An injured Golden Eagle (Aquila chrysaetos) was found entangled in bushes near the vicinity of Balkasar Research Complex, Chakwal, Pakistan. After complete physical examination, a wound on the right wing and closed leg fracture was diagnosed. The successful treatment was done by anti-parasitic and anti-bacterial drugs with careful monitoring. Splint was adjusted after aligning the fractured …

Effects Of Phosphodiesterase 3a Modulation On Murine Cerebral Microhemorrhages, Rachita K. Sumbria, Vitaly Vasilevko, Mher Mahoney Grigoryan, Annlia Paganini-Hill, Ronald Kim, David H. Cribbs, Mark J. Fisher

Pharmacy Faculty Articles and Research

Background: Cerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development.

Methods: The effect of PDE3A pathway inhibition was studied in the inflammation-induced and …