Cell and Developmental Biology Commons^™

The Effects Of Vitamin K On Neuronal Ferroptosis, Chelsey P. Eighmey

Electronic Theses & Dissertations (2024 - present)

Dementia is a crippling illness affecting millions worldwide causing significant public health burdens with long-term care. The lack of treatment options results in many years of suffering for affected individuals and their loved ones who often become primary caretakers. Decades of study have focused on treating dementia with little-to-no success, so an emphasis is needed on attempting to prevent disease progression altogether. This research explored vitamin K as a potential strategy for prevention of dementia onset or progression through the mechanism of suppressing ferroptosis. Ferroptosis is a type of cell death suggested to contribute to the hallmark traits of Alzheimer’s …

Stem Cell-Derived Developmental Models For Translational Evaluation Of Disease And Therapy, Maria B. Paredes-Espinosa

Electronic Theses & Dissertations (2024 - present)

Human development as well as congenital and adult diseases emerge from coordinated interactions among multiple cell types, regulatory programs, and tissue compartments that remain largely unresolved. Conventional simple lineage-restricted in vitro systems poorly capture this complexity. My dissertation uses human stem cell-derived developmental models to study human cardiac morphogenesis and heart diseases and application of a networked neuron platform to explore senescence-associated neurodegeneration impact on Alzheimer’s neurons.

Elongating multi-lineage organized cardiac (EMLOC) gastruloids are a synthetic embryology model that co-generates contractile cardiomyocyte populations alongside mesenchymal, endothelial, epicardial-like, neural crest-associated, and neuronal cells within a shared in vitro developmental environment. Single-cell …

Investigation Of Genx Exposure To Pathways Associated With Colorectal Cancer Risk, Emily J. Ferguson

Theses and Dissertations--Toxicology and Cancer Biology

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in drinking water and food sources, resulting in chronic human exposure. Among these compounds, hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, has been introduced as a short-chain replacement for legacy PFAS such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Although GenX is believed to be a safer alternative, emerging research suggests it can still affect human health.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death in the United States, highlighting the need to better understand environmental …

Uncovering The Mechanism Of Reep2-Mediated Emt-Driven Membrane Trafficking In Lung Adenocarcinoma, Kevin Fulp

Theses and Dissertations--Toxicology and Cancer Biology

Membrane trafficking is frequently disrupted during cancer progression, and the underlying mechanisms remain largely unknown. Currently, no effective drugs target dysregulated membrane trafficking for cancer treatment. Recent evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma (LUAD) employs a membrane trafficking program to coordinate cancer cell invasion and immunosuppression. To further dissect the pro-tumorigenic membrane trafficking program, we initiated an in vivo CRISPRi screen to assess more than 2,000 membrane trafficking-related genes in a syngeneic mouse LUAD model. We identified REEP2, an endoplasmic reticulum (ER) shaping protein, as a novel regulator of EMT-driven membrane trafficking. High REEP2 expression is …

Reep2-Driven Pro-Metastatic Secretion Promotes Lung Cancer Progression, Oluwafunminiyi E. Obaleye

Theses and Dissertations--Toxicology and Cancer Biology

Membrane trafficking plays a critical role in cellular function and is frequently dysregulated in cancer to promote metastasis. In lung adenocarcinoma (LUAD), the epithelial-to-mesenchymal transition (EMT) activating transcription factor, ZEB1, drives a pro-metastatic membrane trafficking program; however, the underlying molecular mechanisms remain poorly understood. Using a CRISPR interference (CRISPRi) in vivo screen of 2,099 membrane trafficking regulators in a syngeneic mouse model of EMT-driven LUAD, we identified REEP2 — an endoplasmic reticulum (ER) shaping protein — as a critical regulator of tumor progression. REEP2 mRNA expression correlates with poor prognosis, EMT signatures, and an immunosuppressive tumor microenvironment in LUAD patients. …

Brief Pulses Of High-Level Fluid Shear Stress Enhance Metastatic Potential And Rapidly Alter The Metabolism Of Cancer Cells, Amanda N. Pope, Devon L. Moose, Guy O. Hudson, Hank R. Weresh, Marion R. Dykstra, Aabha Y. Joshi, Patrick Breheny, Eric B. Taylor, Michael D. Henry

Department of Biomedical and Translational Sciences Faculty Publications

Circulating tumor cells (CTCs) face challenges to their survival, including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade is not well understood. Here, we find that cancer cells exposed to brief pulses of high-level fluid shear stress (FSS) exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer cells exposed to FSS rapidly alter their metabolism in a manner that promotes survival by providing energy for cytoskeletal remodeling …

Characterization Of The Effects Of Atp On Primary Brainstem Glial Cells, Donovan J. Aardema Faigh

Graduate Theses/Dissertations

Migraine and temporomandibular joint disorder (TMD) are debilitating orofacial pain disorders that negatively impact one’s quality of life. These disorders are characterized by elevated levels of adenosine triphosphate (ATP) and activation of central nervous system glial cells that promote and maintain central sensitization and enhance pain signaling in response to inflammatory stimuli. The goal of my study was to characterize the effects of the pro-inflammatory signaling molecule adenosine triphosphate (ATP) on intracellular calcium levels, mRNA levels, and protein expression in astrocytes, microglia, and oligodendrocytes to better understand the role of ATP in promoting central sensitization. To address this goal, primary …

The Effect Of Sex On A-To-I Editing In Skeletal Muscle During Inflammation, Skyler Lee

Graduate Theses/Dissertations

Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional mechanism mediated by ADAR enzymes that can alter RNA sequence, protein function, and gene regulation. Because ADAR1 is upregulated during inflammation and plays a critical role in innate immunity, previous studies investigated the effects of acute inflammation on RNA editing in male and female mice. Lipopolysaccharide (LPS) was used to induce inflammation, and RNA editing levels were examined in the heart, brain, and skeletal muscle. While editing levels in the heart and brain remained unchanged, skeletal muscle exhibited tissue- and sex-specific differences in editing. In this thesis, LPS treatment affected selective editing, increasing …

Synthesis And Characterization Of Succinate Dehydrogenase Inhibitors H2/Z14 And C6/Z96 In Order To Combat Small Cell Lung Cancer, Lauren M. Graves

Honors Undergraduate Theses

The use of ubiquinone inhibitors to combat cancer is a recent development in medicinal science and procedures to efficiently synthesize these drugs remain limited. C6/Z96 and H2/Z14, two succinate dehydrogenase inhibitors, have been previously tested in vitro against NSCLC with positive results. Their similarity to ubiquinone is what makes them a strong candidate for a succinate dehydrogenase inhibitor at the ubiquinone binding site. The heterocyclic scaffolds and substituents are proposed to bind strongly through a combination of electronics, hydrogen-bonding, and fit, allowing them to bind well and prove to be more favorable than ubiquinone when competing for the Q-site. By …

Establishment Of An In Vitro Dss-Induced Epithelial Injury Model To Investigate Il-6 Signaling And Microbial Metabolite Mediated Barrier Recovery, Srijal Kunwar

Graduate Studies Theses and Dissertations 2026

Dextran sodium sulphate (DSS) is widely used in vivo to induce epithelial injury; however, the molecular effects of DSS on intestinal epithelial cells, that investigate inflammatory and metabolic repair mechanisms remain unclear. Here, we establish an in vitro DSS-induced epithelial damage model using differentiated Caco-2 cell monolayer. Exposure to 2.5%(w/v) DSS for 24 hours resulted in significant upregulation of pore forming protein Claudin-2(2.677-fold) and oxidative marker, NOX-1(1.866-fold), accompanied by increased ROS production confirmed via DHE staining. Increased epithelial permeability was observed by TEER analysis, without significant cytotoxicity. Surprisingly, ELISA analysis revealed significant downregulation of IL-6 (p-value …

Evaluating Novel Targeted Combination Therapies For Gastrointestinal Cancers, Joseph A. Goode

Graduate Studies Theses and Dissertations 2026

Gastrointestinal (GI) cancers remain among the leading causes of cancer-related mortality worldwide, with therapeutic resistance continuing to limit the effectiveness of current treatments. Three complementary studies were conducted to identify therapeutic vulnerabilities and evaluate novel combination strategies in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).  First, dual inhibition of fibroblast growth factor receptor 4 (FGFR4) and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling was investigated in PDAC models. A combination of targeted drug treatments reduced viability, clonogenic survival, migration, and suppressed signaling pathways involved in translational control. This supported a functional interaction between FGFR4 and PI3K-mTOR co-activation in …

Epigenetic Modifications In Dedifferentiated Liver Cells To Restore Lost Liver Function, Shreya Sharma

Masters Theses

The goal of the study is to investigate whether the epigenetic modifications can enhance the restoration of liver gene expression in dedifferentiated hepatoma cells or not. For the study, we used dedifferentiated H11 hepatoma cell lines which overexpress one of a panel of introduced candidate liver-enriched transcription factors H11-HNF1a, H11-CREB3L3, H11-CREG1, H11- HHEX, H11-HNF6, and H11-IGFBP1. The cells were treated with the DNA methyltransferase inhibitor 5-azacytidine and the histone deacetylase inhibitor sodium butyrate, both individually and in combination. Gene expression analysis was determined by RT-qPCR, which revealed that while transcription factor overexpression alone produced limited activation, epigenetic modulation, particularly Histone …

Impact Of Cigarette Smoke On Immune And Stromal Cells, Justin Wong

Master's Projects

Cigarette smoke is a plight on human health, being a major contributor to lung diseases. The aryl hydrocarbon receptor (AHR) directs immune regulation and metabolic adaptation in response to environmental toxins. This study investigates transcriptomic changes between wild-type and AHR knockout mouse lung tissue under smoke and air conditions. Single-cell RNA sequencing data were generated by the Butcher Lab and analyzed in Seurat for differential gene expression (DGE) analysis. A two way ANOVA framework was used with DGE analysis to classify genes as smoke induced or suppressed in an AHR dependent or independent manner, and these gene sets were analyzed …

Orexin Receptor Modulation In Amygdalar Stress Circuitry Differentiates Resilient And Vulnerable Phenotypes, Megan Marie John

Dissertations and Theses

Social stress is important for evaluating threats and resource opportunities, however, chronic exposure initiates the onset of psychological disorders, such as anxiety, depression, and post-traumatic stress disorder (PTSD). Stress responsiveness varies between individuals and sexes, resulting in disproportionate diagnoses and ineffective treatment outcomes. Enhancing therapeutic efficacy requires understanding of stress responsivity, phenotype development, and neurocircuitry modifications. Key contributors to stress responsiveness, such as threat of aggression and motivational initiation, influence the development of resilient or vulnerable phenotypes through behavioral and molecular adaptations to stress-related neurocircuitry. The basolateral amygdala (BLA) is a brain region associated with fear learning and integrates stress …

Antibody-Drug Conjugates Beyond Her2 In Non-Small Cell Lung Cancer (Nsclc): Mechanisms, Emerging Targets, And Future Directions, Ahmed Ismail, Akash Desai, George R. Simon, Yanis Boumber

Department of Medicine Faculty Publications

Antibody–drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of …

An Analysis Of Heart Failure Among Cancer Patients In The United States Between 1999 And 2020, Abes A. Bautista Neughebauer, Deepak Talreja, Apostolos Gaitanidis

Department of Medicine Faculty Publications

Background: Cancer and heart failure (HF) are highly prevalent in the population and can co-exist, due to shared risk factors and an aging population. The HF-related mortality burden in cancer patients across in the United States (US) remains poorly understood. The goal of this study is to evaluate the patterns of HF-related deaths among cancer patients in the United States.

Methods: A retrospective analysis was performed using the Centers for Disease Control and Prevention (CDC) WONDER Multiple Cause of Death database between years 1999 and 2020. HF-related deaths were defined as death certificates listing HF as a contributing cause of …

The Importance Of The Proline Residue In The Ldiapa Motif Of Cholera Toxin, Akash Bharathan

Honors Undergraduate Theses

Cholera is currently on its seventh global pandemic, disproportionately affecting developing countries. Vibrio cholerae, the bacterial etiologic agent, is able to cause infection by adhering to intestinal epithelial cells and secreting cholera toxin (CT), an AB-type exotoxin that dysregulates signaling pathways. Previous research by the Teter lab has shown that Hsp90, a host cytosolic chaperone, is required for CT to enter the cytosol where it produces toxic effects. Hsp90 binds to CT at two specific motifs, RPPDEI and LDIAPA. The prolines in the RPPDEI motif are essential for binding, but the proline in the LDIAPA has yet to be …

Single-Cell Transciptomic Analysis Reveals Age-Related Remodeling Of Brain Endothelial Cells, Hai Duc Nguyen, Summer Siddiqui, Diana G. Bohannon, Robert V. Blair, Hong-Wen Deng, Alexandre Prat, Woong-Ki Kim

Microbiology & Molecular Cell Biology Faculty Publications

Blood–brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes—Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2—defined by marker genes Mfsd2a, Plvap, Bmx, Nr2f2, and Vcam1, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial …

Nanoparticle Carriers Enhance The Prophylactic Antiviral Effects Of Dsrna In Vitro And Ex Vivo, Shayne Oberhoffner, Stephanie Dewitte-Orr, Starla Richardson, Leah Haile, Dominique Daniels, Erin Cooper, Aizah Ijaz, Janet Velasquez Perez, Mathilde Peruzzi, Bertrand Collet, Paul Craig, Kristof Jenik

Theses and Dissertations (Comprehensive)

Aquaculture now outpaces traditional capture fisheries as the world population and demand for sustainable protein sources increases. Wild and farmed species are increasingly susceptible to pathogen spread as global temperatures rise and stocking densities increase. Despite the devastating losses experienced by aquaculture due to viral infections, there remain few effective prophylactic antiviral therapeutics. Long double-stranded (ds)RNA is a uniquely viral molecule produced by nearly all viruses during their replication cycle, and its detection by salmonids like rainbow trout (Oncorhynchus mykiss) and chinook salmon (Oncorhynchus tshawytsha) leads to the establishment of a defensive antiviral state. Previous in vitro studies demonstrated a …

Investigating The Immunostimulatory Potential Of Dsrna-Silk Nanoparticle Complexes In Melanoma, Samuel J. Peters

Theses and Dissertations (Comprehensive)

The rate of resistance to immune checkpoint inhibitor treatment in metastatic melanoma is quite high, with an overall rate of 70%. Melanoma achieves these high rates of resistance by suppressing the immune response in the tumour microenvironment (TME), making them immunologically “cold”. The type 1 interferon response could be leveraged to initiate immune responses in melanoma, making their “cold” TMEs “warm” again. Double-stranded ribonucleic acids (dsRNAs) are potent activators of an innate immune response; however, they are susceptible to degradation by nucleases present in the body and need a carrier. Silk nanoparticles (SNPs) are an ideal drug-delivery platform as they …