Disease Modeling Commons^™

Nutrient-Driven Transcription Factor-Dna Interactions And Their Signaling Mechanisms In Metabolic Disease, Evelyn A. Bates

Theses and Dissertations--Nutritional Sciences

Metabolic homeostasis is maintained through tightly coordinated signaling networks that integrate diverse physiological inputs. Central to this regulation are transcription factors, which sense nutrient, hormonal, and vitamin-derived signals and translate them into coordinated gene expression programs. Transcription factor activity is governed by DNA binding, recruitment of coregulatory proteins, and interactions with specific response elements in gene promoters, which allows them to selectively modulate diverse metabolic pathways. Owing to their multifactorial and tunable nature, transcription factors have emerged as promising targets for the treatment and diagnosis of metabolic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). This dissertation explores the molecular …

Disrupted Circadian Rhythms Affect Hallmark Pathologies In Alzheimer’S Disease-Related Mouse Models, Valeria Buzinova

Theses and Dissertations--Molecular and Cellular Biochemistry

Alzheimer’s Disease (AD) is a complex neurodegenerative disease with two hallmark pathologies: extracellular amyloid-b (Ab) and intracellular neurofibrillary tangles (NFTs). Ab is proteolytically processed from amyloid precursor protein (APP) by b-secretase and g-secretase as a monomeric peptide prone to aggregation. Eventually, the aggregate-prone monomers will form dense plaques that are difficult to break down and remove. These plaques begin to deposit into the cortex decades prior to the formation of NFTs and the onset of cognitive decline. NFTs are comprised of hyper-phosphorylated tau. Tau is a protein that serves to promote and stabilize the formation of microtubules. The formation of …

Modeling Inherited Retinal Disease In Zebrafish, Meet Patel

Theses and Dissertations--Biology

Inherited retinal diseases (IRDs) affect millions of people worldwide. Majority of IRDs are caused by degeneration of rod and cone photoreceptor cells (PRCs) due to gene mutations. The overarching goal of my dissertation is to model and evaluate the molecular role of various gene candidates involved in IRDs such as cone rod dystrophy (CRD) and retinitis pigmentosa (RP).

Mutations in CDHR1, a photoreceptor specific cadherin have been associated with CRD and recapitulated in mouse CDHR1 knockouts. However, the molecular function of CDHR1 remains unknown. CDHR1 has been shown to localize at the leading edge of murine rod nascent outer segment …

Inhibiting Pi3k/Akt To Enhance Brain Uptake Of Anticancer Agents In Glioblastoma, Louis Rodgers

Theses and Dissertations--Pharmacy

Glioblastoma (GBM) is the deadliest and most common malignant CNS tumor. Despite advances in understanding its biology and the development of targeted therapies, effective treatment options remain limited. As a result, patient survival rates are dismal, with a 5-year survival rate of only 6.8% and an overall survival of less than two years. This poor outcome is partly due to our inability to treat GBM cells that infiltrate the whole brain. Focal treatments like surgery and radiotherapy alone are insufficient due to these invasive tumor cells. Therefore, chemotherapy following resection and irradiation of the primary tumor is essential to eliminate …

Potential Alzheimer's Disease Plasma Biomarkers, Taylor Estepp

Theses and Dissertations--Epidemiology and Biostatistics

In this series of studies, we examined the potential of a variety of blood-based plasma biomarkers for the identification of Alzheimer's disease (AD) progression and cognitive decline. With the end goal of studying these biomarkers via mixture modeling, we began with a literature review of the methodology. An examination of the biomarkers with demographics and other health factors found evidence of minimal risk of confounding along the causal pathway from biomarkers to cognitive performance. Further study examined the usefulness of linear combinations of biomarkers, achieved via partial least squares (PLS) analysis, as predictors of various cognitive assessment scores and clinical …

Sex Dimorphisms Of Aldosterone And High Salt Induced Aortic Aneurysms In Mice, Xufang Mu

Theses and Dissertations--Pharmacology and Nutritional Sciences

Aortic aneurysms, a permanent enlargement in the aorta, is a devastating disease with a high mortality rate after rupture. Aortic aneurysms exhibit strong sex dimorphisms: men are at higher risk than women while women experience worse outcomes if diagnosed. Currently, the only intervention is by open surgery or endovascular repair, and no drugs are approved for blunting the disease progression. This highlights the needs for mechanistic studies for sex-specific therapeutic targets.

Our lab established the mouse model in which mineralocorticoid receptor (MR) agonist aldosterone induces aortic aneurysms in the presence of high salt in male mice age-dependently, mimicking the aging …

Modeling The Effects Of Adverse Childhood Experiences Using A Mouse Model Of Neglect: Mechanisms Of Adiposity Expansion In Females, Jacqueline Leachman

Theses and Dissertations--Pharmacology and Nutritional Sciences

Adverse childhood experiences (ACEs) are an independent risk factor for chronic disease, including obesity and metabolic syndrome. We have previously shown that a mouse model of early life stress, maternal separation and early weaning (MSEW), exacerbates high-fat diet (HF)-induced obesity only in adult female mice. In agreement, the analysis of several cohorts of participants exposed to ACEs have shown that women are more susceptible to develop obesity than men. Therefore, the aim of this study was to investigate the link between early life stress and obesity in pre-clinical and clinical settings. Male and female MSEW mice fed 1 week a …

Preventing P-Gp Ubiquitination Lowers Aβ Brain Levels In An Alzheimer's Disease Mouse Model, Anika M. S. Hartz, Yu Zhong, Andrew N. Shen, Erin L. Abner, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

One characteristic of Alzheimer’s disease (AD) is excessive accumulation of amyloid-β (Aβ) in the brain. Aβ brain accumulation is, in part, due to a reduction in Aβ clearance from the brain across the blood-brain barrier. One key element that contributes to Ab brain clearance is P-glycoprotein (P-gp) that transports Aβ from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Aβ brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that Aβ₄₀ triggers P-gp degradation through the ubiquitin-proteasome pathway. Consistent with these …

Functional Characterization Of Scaffold Protein Shoc2, Hyein Jang

Theses and Dissertations--Molecular and Cellular Biochemistry

Signaling scaffolds are critical for the correct spatial organization of enzymes within the ERK1/2 signaling pathway and proper transmission of intracellular information. However, mechanisms that control molecular dynamics within scaffolding complexes, as well as biological activities regulated by the specific assemblies, remain unclear.

The scaffold protein Shoc2 is critical for transmission of the ERK1/2 pathway signals. Shoc2 accelerates ERK1/2 signaling by integrating Ras and RAF-1 enzymes into a multi-protein complex. Germ-line mutations in shoc2 cause Noonan-like RASopathy, a disorder with a wide spectrum of developmental deficiencies. However, the physiological role of Shoc2, the nature of ERK1/2 signals transduced through this …

Pattern Discovery In Brain Imaging Genetics Via Scca Modeling With A Generic Non-Convex Penalty, Lei Du, Kefei Liu, Xiaohui Yao, Jingwen Yan, Shannon L. Risacher, Junwei Han, Lei Guo, Andrew J. Saykin, Li Shen, Michael W. Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, Charles D. Smith, Gregory Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Neurology Faculty Publications

Brain imaging genetics intends to uncover associations between genetic markers and neuroimaging quantitative traits. Sparse canonical correlation analysis (SCCA) can discover bi-multivariate associations and select relevant features, and is becoming popular in imaging genetic studies. The L1-norm function is not only convex, but also singular at the origin, which is a necessary condition for sparsity. Thus most SCCA methods impose ℓ₁-norm onto the individual feature or the structure level of features to pursuit corresponding sparsity. However, the ℓ₁-norm penalty over-penalizes large coefficients and may incurs estimation bias. A number of non-convex penalties are proposed to reduce …

Challenges In Modeling Complexity Of Neglected Tropical Diseases: A Review Of Dynamics Of Visceral Leishmaniasis In Resource Limited Settings, Swati Debroy, Olivia F. Prosper, Austin Mishoe, Anuj Mubayi

Mathematics Faculty Publications

Objectives: Neglected tropical diseases (NTD), account for a large proportion of the global disease burden, and their control faces several challenges including diminishing human and financial resources for those distressed from such diseases. Visceral leishmaniasis (VL), the second-largest parasitic killer (after malaria) and an NTD affects poor populations and causes considerable cost to the affected individuals. Mathematical models can serve as a critical and cost-effective tool for understanding VL dynamics, however, complex array of socio-economic factors affecting its dynamics need to be identified and appropriately incorporated within a dynamical modeling framework. This study reviews literature on vector-borne diseases and collects …

Investigation Of The Safety Of Focused Ultrasound-Induced Blood-Brain Barrier Opening In A Natural Canine Model Of Aging, Meaghan Anne O'Reilly, Ryan Matthew Jones, Edward Barrett, Anthony P. Schwab, Elizabeth Head, Kullervo Hynynen

Sanders-Brown Center on Aging Faculty Publications

Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits.

Methods: Aged dogs naturally accumulate plaques and show …

Simulating Within-Vector Generation Of The Malaria Parasite Diversity, Lauren M. Childs, Olivia F. Prosper

Mathematics Faculty Publications

Plasmodium falciparum, the most virulent human malaria parasite, undergoes asexual reproduction within the human host, but reproduces sexually within its vector host, the Anopheles mosquito. Consequently, the mosquito stage of the parasite life cycle provides an opportunity to create genetically novel parasites in multiply-infected mosquitoes, potentially increasing parasite population diversity. Despite the important implications for disease transmission and malaria control, a quantitative mapping of how parasite diversity entering a mosquito relates to diversity of the parasite exiting, has not been undertaken. To examine the role that vector biology plays in modulating parasite diversity, we develop a two-part model framework …

Transcriptional Signatures Of Brain Aging And Alzheimer's Disease: What Are Our Rodent Models Telling Us?, Kendra E. Hargis, Eric M. Blalock

Pharmacology and Nutritional Sciences Faculty Publications

Aging is the biggest risk factor for idiopathic Alzheimer’s disease (AD). Recently, the National Institutes of Health released AD research recommendations that include: appreciating normal brain aging, expanding data-driven research, using open-access resources, and evaluating experimental reproducibility. Transcriptome data sets for aging and AD in humans and animal models are available in NIH-curated, publically accessible databases. However, little work has been done to test for concordance among those molecular signatures. Here, we test the hypothesis that brain transcriptional profiles from animal models recapitulate those observed in the human condition. Raw transcriptional profile data from twenty-nine studies were analyzed to produce …

Chronic Pancreatitis, Pain, And Anxiety In An Alcohol And High Fat Mouse Model, Tiffanie Clinkinbeard

Theses and Dissertations--Gerontology

Homeodynamic space (HDS) shrinks as vulnerability increases with aging and repeated damage to the cells. HDS is lost in alcoholic pancreatitis patients due to overconsumption of alcohol, smoking, and high fat diets. Etiologically relevant animal models for study of chronic pancreatitis (CP) are needed. In order to begin filling this gap a central purpose of this dissertation research was to examine relationships between the alcohol and high fat diet (AHF) and pancreatitis with attention to hypersensitivity and anxiety-like behaviors. The AHF diet induced pancreatitis described here etiologically mimics human risk factors of AHF consumption for advancement to alcoholic CP.

In …

The Role Of Angiotensinogen In Atherosclerosis And Obesity, Congqing Wu

Theses and Dissertations--Nutritional Sciences

Angiotensinogen is the only known precursor in the renin-angiotensin system, a hormonal system best known as an essential regulator of blood pressure and fluid homeostasis. Angiotensinogen is sequentially cleaved by renin and angiotensin- converting enzyme to generate angiotensin II. As the major effector peptide, angiotensin II mainly function through angiotensin type 1 receptor.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and more recently renin inhibitors are widely known as the 3 classic renin-angiotensin system inhibitory drugs against hypertension and atherosclerosis. Here, we developed an array of regents to explore the effects of angiotensinogen inhibition. First, we demonstrated that genetic deficiency of …

Dopamine And Glutamate Dysfunction In A Rodent Model Of Attention-Deficit/Hyperactivity Disorder: Implications For Future Neuropharmacology, Erin M. Miller

Theses and Dissertations--Neuroscience

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common disorders of childhood. It is theorized to be caused by catecholamine dysfunction in the striatum (Str) and frontal cortex (FC). The spontaneously hypertensive rat (SHR) has been used as a model for ADHD because of its attention deficits, impulsiveness, and hyperactivity. Prior studies of dopamine (DA) in the Str and FC have revealed conflicting results in the SHR compared to control, indicative of a need for a better understanding of DA dynamics in this model. In addition to the DA hypothesis, studies have begun implicating glutamate in the etiology of ADHD. …

Diet-Induced Obesity: Dopaminergic And Behavioral Mechanisms As Outcomes And Predictors, Vidya Narayanaswami

Theses and Dissertations--Pharmacy

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to …