Diseases Commons^™

Pattern Dynamics And Stochasticity Of Brain Rhythms And Spike Trains In A Tauopathy Mouse Model Of Alzheimer’S Disease, Clarissa M. Hoffman

Dissertations and Theses (Open Access)

Systems neuroscience posits that every aspect of perceived physical reality, every aspect of animal and human behavior, and every cognitive phenomenon emerges from patterns of neuronal activity. While most researchers embrace this idea, there are major difficulties in describing and analyzing these complex neuronal dynamics—spike flows produced by cells ensembles, synchronized extracellular field oscillations, and other patterns—which limits our understanding of how the activity of individual neurons and the whole-animal cognition and behavior might be connected. In particular, we lack the approaches and even the semantics for connecting the individual cell outputs and the integrated results of their activity. Current …

Integrating Bulk And Single-Cell Transcriptomics To Investigate Intratumor Heterogeneity, Shuai Guo

Dissertations and Theses (Open Access)

Cancers are heterogeneous mixtures of tumor and surrounding cells, where each component comprises multiple distinct sub-types and/or states. Understanding the cell-type-specific contributions is critical for advancing cancer biology, yet high-throughput expression profiles from tumor tissues only represent combined signals from all diverse cellular sources. Bulk deconvolution with single-cell/nucleus (sc/sn) RNA-seq data has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns, yet the technological discrepancy across sequencing platforms limits accuracy.

To systematically evaluate the impact of platform discrepancies on bulk deconvolution, we first generated a benchmark dataset of 24 healthy retinas with paired bulk and …

Microbial Metabolite Regulation Of Microglial Ahr Signaling In Alzheimer’S Disease, Ghalya E. Alrousan

Dissertations and Theses (Open Access)

Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, neuroinflammation, and cognitive decline. Recent evidence suggests that systemic factors, particularly the gut microbiota and its metabolites, play a significant role in shaping brain immune responses, including microglial activation. However, the mechanisms linking gut dysbiosis to microglial dysfunction in AD are poorly understood. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsive to tryptophan metabolites, has recently gained attention as a key regulator of neuroinflammation and microglial function. I hypothesize that the loss of beneficial microbial AHR ligands, specifically indole derivatives, during aging and AD …

Expanding Inducible Epithelial Resistance Against Pneumonia: Novel Virus, Novel Receptor, Michael Longmire

Dissertations and Theses (Open Access)

Pneumonia is the leading infectious cause of death worldwide and presents a continuing risk among immunocompromised patients. Our work has been focused for many years on the phenomenon of inducible epithelial resistance, where activation of the innate immune response in the airway epithelium is necessary and sufficient to produce a pathogen-killing but self-protective environment to prevent severe disease. Inducible resistance is pathogen-agnostic and has been demonstrated against an array of respiratory infections. We achieve this using a combination of pattern recognition receptor agonists – Pam2CSK4 and ODN M362 being the current formulation – which produce synergistic levels of pathogen reduction …

The Role Of Ucp2 In Pancreatic Cancer Metabolism And Its Potential As A Radiosensitizer, Emily Rieff

Dissertations and Theses (Open Access)

Uncoupling protein 2 (UCP2) is a mitochondrial protein that regulates the flow of protons down the gradient established by the electron transport chain (ETC) without generating ATP, thus uncoupling the proton gradient from ATP generation. In tumors, specifically pancreatic cancer (PDAC), the ETC is highly stimulated to generate the copious ATP needed by the tumor to grow. However, extended ETC use increases reactive oxygen species (ROS), and if left unchecked, results in cell death. To evade this, PDAC employs antioxidant strategies, including upregulating UCP2 in tumor cells. In addition to its uncoupling function, UCP2 indirectly controls ROS levels by maintaining …

Rod Photoreceptor Regeneration In A Zebrafish Model With Retinitis Pigmentosa, Eyad Shihabeddin

Dissertations and Theses (Open Access)

A cellular hallmark of inherited retinal degenerative diseases is progressive loss of photoreceptors until one is completely blind. Unlike mammalian models, Zebrafish have the ability to naturally regenerate their neurons after injury or disease is detected. We have generated a zebrafish model with the most common autosomal dominant form of the inherited retinal degenerative disease known as Retinitis Pigmentosa. We utilize immunohistochemistry, single-cell RNA sequencing, several analysis tools, behavioral assays and oligonucleotides to characterize our zebrafish model and identify the transcription factors necessary for rod photoreceptor regeneration. We show that our zebrafish model has continuous degeneration and regeneration of rod …

Uncovering A Fundamental Mechanism Underlying Female Oocyte Quality And Rasopathies Using C. Elegans As A Model System, Han Bit Baek

Dissertations and Theses (Open Access)

Signaling pathways are molecular networks that allow cells to communicate between and within themselves. They are crucial for the coordination of diverse cellular processes and are the molecular mechanism in which cells sense and respond to their environment. RAS (Rat Sarcoma) is a small GTPase that transmits extracellular growth factor signals through a downstream kinase cascade and ERK (Extracellular-signal regulated kinase) is the terminal kinase, and it controls cellular processes such as proliferation, differentiation, and survival by phosphorylating its downstream effectors. This post translational modification regulates the effector by modulating its activity, levels, and/or interaction with other molecules. Given the …

Exploring The Immunologic Consequences Of Atrx Deficiency In Glioma, Benjamin Whitfield

Dissertations and Theses (Open Access)

ATRX is a key chromatin regulator that is frequently mutated across multiple cancer types. One of the most common ATRX-mutated tumor types is the adult-type glioma, IDH-mutant, Astrocytoma. It is known that ATRX mutation leads to increases in DNA damage, replication stress, and global epigenetic regulation at a cell level; however, less is known about the impact of ATRX mutation on immune signaling. Furthermore, little is known about the interaction of ATRX loss with gain-of-function mutations in IDH. In this paper we set out to explore the impact of ATRX loss on immune signaling in gliomas, both in the context …

An Investigation Into The Potential Of Cell Therapies For Acute Myeloid Leukemia (Aml) Treatment, Amanda Eckstrom

Dissertations and Theses (Open Access)

Despite recent advances in acute myeloid leukemia (AML) treatment, curative rates remain poor with high rates of relapse and many patients are unable to tolerate the intensive chemotherapy standard of care regimen. Cell therapies have shown great success against hematologic malignancies but face several challenges including treatment-related toxicities and human-leukocyte antigen (HLA) matching. Natural killer (NK) cells and gamma delta (γδ) T cells offer alternative effector cell options for cell therapies that do not require HLA-matching and have shown low toxicity in previous studies. In this project, we sought to evaluate FT538 induced pluripotent stem cell-derived NK (iPSC-NK) and donor-derived …

Smooth Muscle Cell Stress Response: Essential In Atherosclerotic Pathogenesis, Pujun Guan

Dissertations and Theses (Open Access)

Atherosclerosis remains the leading cause of death worldwide. Recent research using lineage tracing and single-cell RNA sequencing unveiled a previously undescribed and prominent role of smooth muscle cells (SMCs) in atherosclerotic plaque formation. SMCs undergo complex phenotypic modulation characterized by de-differentiation of SMCs and heterogeneously increased expression of markers for macrophages, fibroblasts, chondrocytes, and mesenchymal stem cells as plaques form. Cultured SMCs exposed to exogenous cholesterol mimic many of the phenotypic changes associated with plaque formation, and our lab determined this SMC modulation is driven by cholesterol entering the endoplasmic reticulum (ER) and triggering ER stress and PERK signaling. Further, …

Investigating The Role Of Insulin-Like Signaling In Paclitaxel-Induced Nociceptive Hypersensitivity Using Drosophila Melanogaster, Sreepradha Sridharan

Dissertations and Theses (Open Access)

Paclitaxel (PTX), a chemotherapeutic that alters microtubule dynamics, is known to induce nociceptive hypersensitivity and sensory neuron damage in human patients and in Drosophila larvae. We used a modified feeding protocol to establish a genetically tractable Drosophila model of PTX-induced hypersensitivity. Larvae fed PTX exhibited hypersensitivity to thermal and mechanical stimuli. Thermal hypersensitivity was observed at low concentrations of PTX (even below 1 μM per ml of food), begins within 8 hours of PTX feeding, and did not completely resolve at the larval stage. Live imaging of peripheral thermal nociceptors showed that this hypersensitivity precedes observable neuronal damage. At low …

Delineating Metastasis In Mss Colorectal Cancer By Single - Cell Rna Sequencing, Shuangjie You

Dissertations and Theses (Open Access)

Colorectal cancer Colorectal Cancer (CRC) is the leading cause of cancer-related deaths, with the majority of these deaths occurring after metastases. In this study, we used single-cell RNA transcriptome sequencing to characterize the cellular and molecular features of primary CRC and colorectal liver metastases (CRLM). Analysis of 130 samples revealed significant heterogeneity in the tumor microenvironment (TME) characterized by a diversity of cancer-associated fibroblasts, immune cells, and endothelial cell populations. Notably, we identified different CAF subtypes, including inflammatory (iCAFs), matrix(mCAFs), complement (cCAFs), and vascular (vCAFs). iCAFs were enriched in primary tumors expressing higher levels of inflammation-associated genes, whereas mCAFs were …

Exploring The Role Of The Arginine-Methylation Writer-Reader Pair Prmt5/Snd1 In Jak2-Mutant Myeloproliferative Neoplasms, Rocio Rubiano

Dissertations and Theses (Open Access)

Myeloproliferative neoplasms (MPNs) are a hematopoietic disease characterized by hyperproliferation of cells of the myeloid lineage for which current therapeutic options are limited. Discovered in 2005, the JAK2V617F mutation is the most common driver mutation in BCR-ABL negative MPNs, resulting in constitutive activation of the JAK2 protein and the JAK-STAT signaling pathway. A role for the methyltransferase activity of Protein Arginine Methyltransferase 5 (PRMT5) has been proposed in JAK2-mutant MPN, highlighting both a mechanism through which this mutation can drive disease progression and a potential mode of therapeutic intervention. Staphylococcal Nuclease Domain-Containing Protein 1 (SND1) is the effector molecule responsible …

Genetic Analysis Of Kmt2d Loss In Tumorigenesis Using Genetically Engineered Mouse Models, Yingda Jiang

Dissertations and Theses (Open Access)

The Cancer Genome Atlas Program (TCGA) has discovered multiple tumor suppressors that are commonly mutated across a variety of human cancers, such as chromatin regulators in COMPASS and SWI/SNF complexes. KMT2D, a histone H3K4 methyltransferase in the COMPASS complex, is frequently mutated in human lymphoma, melanoma, and epithelial carcinoma. Biochemically, KMT2D shapes the cellular enhancer landscape as the major writer of the putative enhancer mark H3K4me1. Given the critical role of cellular enhancer landscape in determining cellular lineage in embryonic development, it is unknown whether enhancer dysregulation caused by KMT2D loss leads lineage switch of tumor cells, which has …

Evaluation Of Myogenic Differentiation Potential Of Bmd Ipscs In Vitro And The Effect Of Ubiquitination Inhibitors On Dystrophin Stability In Vivo, Muchen Liu

Dissertations and Theses (Open Access)

Background: Muscular dystrophies are heterogeneous groups of inherited diseases leading to progressive muscular weakness and degeneration. In the case of Becker muscular dystrophy (BMD), non-disrupting mutations of the DMD gene reading frame is the causative defect. By the age of 30s, about 60 to 70% of BMD patients develop cardiomyopathy, which is often lethal. Unfortunately, there is currently no cure for BMD. Meanwhile, improvement of dystrophin stability by repressing polyubiquitination is a promising strategy. The application of human iPSCs in tissue regeneration also serves as a potential therapeutic strategy. This study aims to test the efficacy of selected drugs interfering …

In Vivo Examination Of Peripheral Drivers Of Alzheimer’S Disease, Celso Catumbela

Dissertations and Theses (Open Access)

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and predominantly affects elderly populations. This disease is well known for its effects on the brain, but a wealth of clinical reports show that dementia can also modify, or be modified by, various peripheral and systemic processes. Yet, the pathological contribution of peripheral comorbidities to AD remains to be fully understood. In an attempt to address some knowledge gaps, we characterized the cerebral and peripheral pathology in mice with history of either liver injury or sepsis. In the former subjects, we found that even in the absence of genetic risk …

Mismatch Repair Deficient Neoantigen And Associated Circulating T-Cell Receptor Repertoires In Lynch Syndrome, Ana Bolivar

Dissertations and Theses (Open Access)

Lynch Syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome. It constitutes the perfect model to understand DNA mismatch repair deficient (MMRd) carcinogenesis, which underlies 15% of early-stage CRC. LS patients develop MMRd tumors with high loads of shared neoantigens (neoAgs), which are recognized by the immune system. Previous research has concentrated on discovering neoAgs and their potential as targets for vaccines in LS patients. However, these studies have primarily identified shared neoAgs from cancers, lacking detailed information on targetable neoAgs present in precancerous lesions. Understanding this landscape of pre-cancer derived neoAgs is crucial for intercepting cancer development …

Uncovering Capillary Endothelial Cells Response During Lung Injury-Repair, Celine Shuet Lin Kong

Dissertations and Theses (Open Access)

Once thought to be a homogenous population, capillary endothelial cells (ECs) have embodied organotypic specialization and heterogenous properties, both during homeostasis and tissue injury. In the lung, capillary ECs consist of two distinct populations, CAP1 and CAP2s; how each population responds to diverse tissue injury is incompletely understood. In this thesis, I report the induction and function of a truncated isoform of Ntrk2, Ntrk2^-tk (lacking the tyrosine kinase domain) in multiple injury models. Using a combinatorial approach of single-cell multiome, mouse genetics and viral infection models, I found that Ntrk2^-tk is broadly induced in CAP1s after the initial …

Acute Pain Prediction In Oral Cavity And Oropharyngeal Cancer Patients Receiving Radiation Therapy, Vivian Salama

Dissertations and Theses (Open Access)

Oral-Cavity and oropharyngeal cancers (OC/OPC) are types of head and neck cancers that are increasing in incidence domestically. Radiation therapy (RT) is crucial in OC/OPC management. Pain is a common and challenging symptom for most patients during therapy, as nearly all patients undergoing locoregional RT in OC/OPC require analgesia for acute iatrogenic pain. Moreover, about 45% of long-term survivors report chronic pain, with more than 10% exhibiting severe chronic pain. Pain control is challenging due to the multifactorial clinical, molecular, and cellular etiology of cancer/therapy pain, as well as variation in pain assessment and the non-uniform management of pain between …

Cord Blood-Derived Invariant Natural Killer T Cells As A Platform For Allogeneic Chimeric Antigen Receptor Cell Therapy, Maison Grefe

Dissertations and Theses (Open Access)

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematopoietic malignancies achieving >50% complete response rates in numerous refractory/relapsed B cell malignancies. However, there are challenges that hinder CAR-T efficacy and bar the broader use of this therapy in patients. One approach to address these challenges is to create a safe allogeneic CAR cell product by using cells that do not cause graft versus host disease (GvHD). Invariant natural killer T (iNKT) cells are an ideal candidate as they are restricted to the monomorphic CD1d protein in contrast to HLA restricted αβ-T cells and therefore are safe in …

Inclusion Of Adoption As A Pregnancy Management Option In Prenatal Genetic Counseling Practice, Emma Billings

Dissertations and Theses (Open Access)

Prenatal genetic counselors are essential to providing education, psychosocial support, and guidance on pregnancy options to patients who receive a fetal diagnosis of an anomaly or genetic condition. Therefore, genetic counselors should be well-educated on comprehensive pregnancy management options consisting of parenting, abortion, and adoption. The landscape of adoption education in genetic counseling practice was last characterized in 2010 by Perry and Henry, revealing substantial variability in both the inclusion of adoption-specific education in genetic counseling program (GCP) curricula and the discussion of pregnancy options with patients in prenatal practice. As a result, the authors published a call to action …

Retinoid X Receptor As A Mediator Of Post Stroke Recovery By Reversing Age-Associated Phenotypes Of Microglia/Macrophages, Shun-Ming Ting

Dissertations and Theses (Open Access)

After stroke, microglia (MG) and blood-derived macrophages, together (MF), clear dead cells and cellular debris in the infarcted brain through phagocytosis. However, the phagocytic capability of MF declines with age. Age-related changes in MF phenotype also include overactive inflammatory responses to stroke-induced brain injury, altogether resulting in poor recovery after stroke. Retinoid-X-receptor (RXR) is a pleiotropic transcription factor. Our studies suggest that RXRa enhances MF phagocytic functions, reduces inflammatory responses, and improves post-stroke recovery. To establish phenotypes of aging MF, MG were MACS-sorted from the brains of young adults (2-4 months old) and aged (18-20 months old) mice for transcriptomic …

Interrogating Therapeutic Resistance To Oncogenic Krasg12c-Based Therapies In Colorectal Cancer, Oluwadara Coker

Dissertations and Theses (Open Access)

Colorectal cancer is the second leading cause of cancer-related deaths and the third most common cancer in the United States. Although KRAS is mutated in 50% of patients with metastatic CRC (mCRC), it has historically been a challenging therapeutic target. The recent approval of novel covalent inhibitors selective for KRASG12C mutation have entered the clinic, which has not only marked a major milestone in cancer drug discovery but has also intensified efforts to directly target other KRAS mutations that have also successfully entered the clinic. However, treatment-associated resistance mechanisms have long threatened to attenuate clinical benefit through either adaptive or …

Effect Of Body Mass Index Percentile On Complicated Appendicitis, Postoperative Complications And Health Service Utilization Among Pediatric Patients In The United States, Nutan Hebballi

Dissertations and Theses (Open Access)

While overweight and obesity have been extensively studied for complicated appendicitis, postoperative complications, and health service utilization, the effects of being underweight are unknown. This dissertation assesses the associations between the body mass index (BMI) spectrum with complicated appendicitis, postoperative complications, and healthcare service utilization in pediatric patients.  A retrospective review of pediatric patients who underwent appendectomy surgery (01/01/2016-12/31/2020) was conducted using the National Surgical Quality Improvement Program database. Computed age and gender-specific BMI percentiles were categorized into underweight, normal weight, overweight and obese. The 30-day postoperative complications were grouped into minor, major, and any. Healthcare service utilizations were compared …

A Larval Zebrafish (Danio Rerio) Model Of Adherent-Invasive Escherichia Coli Infections, Erika Flores, Erika Flores

Dissertations and Theses (Open Access)

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a broad term for chronic intestinal disorders that severely impact patient morbidity and quality of life. The global prevalence of IBD is rising, with over one million patients affected in the US alone. Adherent-invasive E. coli (AIEC) is a pathobiont frequently found in IBD biopsies. AIEC adhere to and invade epithelial cells, and can survive inside macrophages in vitro. However, how AIEC contributes to IBD in vivo remains unclear. Here a larval zebrafish (Danio rerio) model of AIEC was established, which facilitates the study of the …

Investigating The Role Of Il-10 Producing Nkt Cells In Prevention Of Graft Versus Host Disease, Drew Boagni

Dissertations and Theses (Open Access)

The standard curative treatment for hematologic malignancies is allogeneic stem cell transplantation (ASCT), in which the patient’s immune system is replaced with that of a healthy donor. This can lead to cure through the graft versus leukemia (GVL) effect but can also cause graft versus host disease (GVHD), which is characterized by systemic inflammation and organ damage mediated by dysregulated donor T cells. Preclinical studies have shown invariant natural killer T cells (iNKT) cells can prevent GVHD while preserving GVL. iNKT cells are unconventional T cells which recognize glycolipid antigens presented in the context of CD1d. Upon activation, they secrete …

The Cx3cl1-Cx3cr1 Chemokine Axis Contributes To Tumor Immune Evasion And Its Blockade Enhances Responses To Anti-Pd-1 Immunotherapy, Apoorvi Chaudhri

Dissertations and Theses (Open Access)

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. While CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration, the mechanisms employed by this axis on these cells to mediate immune suppression remain poorly understood. Here, we explore the immune evasion strategies implemented by this axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of mediators to attract …

Adipocytes And Innate Immunity In Systemic Sclerosis, Nancy Wareing

Dissertations and Theses (Open Access)

Systemic sclerosis (SSc; scleroderma) is a chronic systemic autoimmune and connective tissue disorder characterized by vasculopathy, autoimmune phenomena, and widespread fibrosis. Skin thickening and tightening is the cardinal feature of SSc and is responsible, in part, for the considerable morbidity of this disease. There are currently no targeted treatments for skin manifestations in SSc, primarily due to our fragmented understanding of its pathophysiologic mechanisms. In PART I, we report a previously unappreciated link between aberrant expression of the developmental gene sine oculis homeobox homolog 1 (SIX1) in skin-associated adipocytes in SSc skin and the early loss of dermal white adipose …

The Diagnostic Odyssey Of Hypermobile Eds Patients: Diagnosis, Clinical Expectations, And Psychosocial Concerns, Madeline Alpar

Dissertations and Theses (Open Access)

Background: Ehlers-Danlos syndrome (EDS) is a highly variable, heritable connective tissue disorder. Hypermobile EDS (hEDS) is the most common subtype of EDS and has no identifiable underlying genetic etiology. Patients with clinical features of hEDS face a long diagnostic odyssey due to lack of genetic testing and wide clinical heterogeneity. Additionally, recent research has shown that genetic institutions limit evaluations for suspected hEDS, adding another barrier to care.

Methods: We developed an online patient survey to explore the diagnostic odyssey of hEDS for those who were diagnosed with or suspicious for hEDS. This survey included sections on demographics, diagnostic information …

Targeting Metabolic Alterations Associated With Smooth Muscle Α-Actin Pathogenic Variant Attenuates Moyamoya-Like Cerebrovascular Disease, Anita Kaw

Dissertations and Theses (Open Access)

Heterozygous pathogenic variants in ACTA2, encoding smooth muscle α-actin (α-SMA), predispose to thoracic aortic aneurysms and dissections. De novo missense variants disrupting ACTA2 arginine 179 (p.Arg179) cause a multisystemic disease termed smooth muscle dysfunction syndrome (SMDS), which is characterized by early onset thoracic aortic disease and moyamoya disease-like (MMD) cerebrovascular disease. The MMD-like cerebrovascular disease in SMDS patients is marked by bilateral steno-occlusive lesions in the distal internal carotid arteries (ICAs) and their branches. To study the molecular mechanisms that underlie the ACTA2 p.Arg179 variants, a smooth muscle-specific Cre-lox knock-in mouse model of the heterozygous Acta2 R179C variant, termed …