Digital Commons Network^™

A Signal To Divide: Apoptotic Extracellular Vesicles As Carriers Of Mitogenic And Immunogenic Signals, Safia Essien, Safia Essien

Dissertations & Theses (Open Access)

Efficient replacement of dead cells in epithelial tissue is crucial for maintaining barrier function and tissue homeostasis. Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss and maintain overall cell numbers in normal physiology and cancer. While dying cells can transmit instructive cues to neighboring cells, the molecular mechanisms that induce cell division are not well understood. Recent evidence suggests that apoptotic bodies (ABs) or apoptotic extracellular vesicles (AEVs) mediate cell-to-cell communication and carry diverse biologically active cellular cargo which can influence cell proliferation. This dissertation visualizes and characterizes AEVs in larval zebrafish and …

Genomic Characterization Of Adolescent And Young Adult Cancers: Investigation Of Ewing Sarcoma Susceptibility And Chornobyl Thyroid Tumors, Olivia Lee

Dissertations & Theses (Open Access)

Adolescent and young adult (AYA) cancers, diagnosed between the ages of 15 and 39, can exhibit distinctive genetic and molecular characteristics. Reported epidemiologic findings and treatment outcomes based on pediatric and adult cancer studies are often not suitable for application to the AYA population, underscoring the need for more thorough genomic research. Advances in sequencing technologies have enabled comprehensive analyses of complex genomic characteristics of AYA cancers, crucial for understanding the underlying biology of these malignancies. Here, I have utilized advanced sequencing techniques and integrated analytic approaches to describe important genomic features in two different AYA cancer types: Ewing Sarcoma …

Cortical Representation Of Learning Social Interactions In Freely Moving Non-Human Primates, Melissa Franch

Dissertations & Theses (Open Access)

The motivation and capacity to be social is necessary for human survival. Successful learning of complex, prosocial behavior stems from the ability to perceive and respond to visual cues, such as the body language and facial expressions, from others in our environment. This dependence on visual information to guide social interaction is especially true for humans and non-human primates. Although recent studies in primate neurophysiology discovered neurons that can encode socially relevant variables, like reward and social actions, the underlying neural mechanisms of learning advanced social concepts, such as cooperation, are not well understood. Further, previous work has identified …

A Cancer-Specific Study On The Differentially Expressed Protein-Protein Interactions Of Fumarate Hydratase, Sydney Lac

Dissertations & Theses (Open Access)

Fumarate hydratase (FH) is an enzyme used in the Krebs Cycle to convert fumarate to malate, and it is controlled by the FH gene. In this paper, we will investigate its role in Uterine Corpus Endometrial Carcinoma (UCEC) and how FH-deficient cells affect tumorigenesis. It is well-established that FH has been extensively studied in connection with renal cell carcinoma, skin and uterine leiomyomas, pheochromocytoma, and paraganglioma. However, we aim to construct an interaction network of significant genes related to the FH gene under conditions of FH deficiency in the Kreb Cycle. Creating an interactive network that illustrates the interconnectedness of …

Development Of Novel Methods To Study Host-Microbe Interactions In The Larval Zebrafish Gastrointestinal Tract, Anh K. Trinh Nguyen

Dissertations & Theses (Open Access)

The dynamic nature and inaccessible location of the intestine pose significant challenges to the study of intestinal physiology and pathology. Zebrafish larvae, possessing optical transparency and genetic tractability, offer an accessible and clinically relevant model for investigating dynamic events in the intestine via time-lapse imaging. In the first part of this work, I discuss our efforts to optimize the parameters of a foodborne infection assay using paramecia as a vehicle. This method provides an effective, high-throughput alternative to infection via immersion or oral gavage, and replicates the most common route of transmission of gastrointestinal (GI) infection in humans. The foodborne …

Role Of The Immune System In The Modulation Of The Mmr-Deficient Intestinal Stem Cell Niche, Shepard Conner

Dissertations & Theses (Open Access)

Mismatch Repair (MMR) is a crucial DNA repair system to maintain genomic integrity in cells that is integrated by specific genes including MLH1, MSH2, MSH6, and PMS2. These genes play a critical role in repairing errors that occur in base pairing by stabilizing the genetic material. When the MMR system fails to correct those errors, MMR deficiency occurs where monoallelic mutations in the MMR genes result in a condition known as Lynch Syndrome (LS). LS makes up approximately 3% of all colorectal cancer (CRC) and is regarded as a hereditary form of CRC, which progresses from MMR-deficient …

Oncogenic Kras And Telomere Biology In Crc Progression, Ronald Depinho

Dissertations & Theses (Open Access)

While colorectal cancer (CRC) patients diagnosed with localized stage disease (as defined by SEER) have a 5-year survival rate of 90%, this rate plunges to 14% for patients diagnosed with metastatic CRC. Consequently, there is an immediate imperative to elucidate the mechanisms that drive the transition to advanced CRC.

Human CRCs carrying oncogenic mutations in the KRAS oncogene, henceforth referred to as KRAS*, exhibit a 25% higher propensity for developing liver metastases. Similarly, in our CRC mouse model, engineered with an inducible Kras* transgene and conditional null alleles of Apc and Tp53 (referred to as iKAP), KRAS* has been …

Identification And Delineation Of Neuronal Pathways Underlying Hypophagia, Jing Cai

Dissertations & Theses (Open Access)

In terms of metabolism, eating disorders manifest in two extreme directions: overnutrition, which can lead to obesity, and malnutrition, which can result in underweight or even starvation. Both extremes compromise the quality of life. According to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) standard, eating disorders affect up to 17.9% of young women and 2.4% of young men. Although eating disorders are primarily defined as mental disorders rather than metabolic disorders, they are intertwined with complex emotions and sensory perceptions. However, in contemporary animal research related to eating disorders and feeding behaviors, the majority of neuroscientists still examine …

A Study Of The Snd1/Prmt5 Axis In Liver Cancer By Genetic Mouse Models, Tanner Wright, Tanner Wright

Dissertations & Theses (Open Access)

Arginine methylation is an essential post-translational modification (PTM) in cells. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme that catalyzes symmetric dimethyl arginine (SDMA) and requires methylosome protein 50 (MEP50) for stability and enzymatic activity which are necessary for life and development. Effector proteins bind different types of PTM’s to facilitate signaling. Staphylococcal nuclease Tudor domain containing 1 (SND1) is an effector that specifically binds SDMA via its single C-terminal Tudor domain. Both SND1 and PRMT5 have been implicated in hepatocellular carcinoma (HCC). SND1 has been confirmed as a driver of HCC using genetically engineered mouse models (GEMMs), though, …

Genetic Analysis Of Crossover Defective Mouse Spermatocytes Reveals Discrete Crossover Precursor Intermediates, Tolkappiyan Prem Kumar

Dissertations & Theses (Open Access)

In healthy, non-replicating somatic cells of diploid organisms, like humans and mice, there are two copies of each chromosome, one from each parent. However, the germ cells of these organisms, the oocytes, and the sperm, have only one copy of each chromosome, thus ensuring that when haploid oocytes and sperm fuse to form a zygote, a diploid number of chromosomes is restored. The reduction of a diploid number of chromosomes to a haploid number of chromosomes takes place during meiosis. The meiotic cell cycle consists of two rounds of cell division, Meiosis I and Meiosis II. Meiosis I create haploid …

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

Dissertations & 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 …

Therapeutic Potential Of Prmt5 And Mat2a As Synthetic Lethal Targets In Mtap-Deficient Gbm Tumors, Yasaman Barekatain

Dissertations & Theses (Open Access)

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is a frequent genetic alteration found in approximately 15% of all human cancers, including glioblastoma, pancreatic cancer, mesothelioma, urothelial bladder carcinoma, and lung squamous cell carcinoma. MTAP is a critical metabolic enzyme in the methionine salvage pathway responsible for the breakdown of methylthioadenosine (MTA). As a result, MTAP-deleted cells cannot metabolize MTA, leading to the accumulation of MTA. High levels of MTA in MTAP-deleted cells partially inhibit the activity of protein arginine methyltransferase 5 (PRMT5), making these cells sensitive to PRMT5 and MAT2A inhibition. Although elevated levels of MTA in …

Landscape Of Ecdna-Borne Non-Coding Rnas In Glioblastoma, Dexin Yang

Dissertations & Theses (Open Access)

Recent advances in cancer genetics found that strong oncogene transcription can occur on a form of non-chromosome DNAs that is often amplified to tens or hundreds of copies, and that can exist in more than half of cancer types. This type of genetic material was termed extrachromosomal DNA (ecDNA). ecDNA appears to be epigenetically highly accessible and transcriptionally active compared with chromosomal DNA, which may partially underlie their critical roles in driving oncogene overexpression and cancer evolution. However, the full molecular mechanisms and regulators that confer the exceptional transcriptional activity of ecDNA-associated genes are incompletely understood.

Enhancers are key genetic …

Acute Manipulation Of Erna Level For Dissecting Its Roles In Transcriptional Regulation, Lanxin Bei

Dissertations & Theses (Open Access)

Enhancers are the central genetic elements controlling cell-type and state specific transcription programs to dictate cell fates during development. Mechanistic understanding of enhancer action is important for both biology and disease research. In the human genome, more than 60k human enhancers were found to produce non-coding transcripts named enhancer RNAs (eRNAs). These created a new challenge to understand enhancer functions, which now are not only DNA elements that promote transcription but also RNA-producing transcription units themselves. Importantly, deregulation of eRNAs was associated with various diseases such as cancer, immune disorders, and neurodegeneration. However, the direct role of eRNAs in transcriptional …

Protein L Functionalized Microparticles For Early Detection Of Surface Markers In Heterogeneous Colorectal Lesions, Saleh Ramezani

Dissertations & Theses (Open Access)

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths among both men and women worldwide, a statistic that can be improved with early detection. Increased understanding of the tumor landscape has identified surface antigens that can be utilized to distinguish normal and cancerous tissue lining the colonic lumen. Use of antibodies conjugated to nano/micromaterials offers a means to detect these antigens, however, the heterogeneous nature of tumors makes it unlikely that antibodies against a single antigen will have sufficient sensitivity and specificity to detect all tumors. A versatile micromaterial able to be functionalized with more than one targeting …

Role Of Il-17/Il-17ra Signaling In The Pancreatic Tumor Microenvironment, Susana Castro Pando, Susana Castro Pando

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths. PDAC is characterized by the early establishment of a highly immunosuppressive fibro-cellular tumor microenvironment (TME). Our research has revealed the important role of IL-17 in the development and progression of pancreatic cancer, yet the specific cellular compartment responsible for IL-17-mediated tumor promotion remains unknown. We generated a transgenic mouse model with pancreatic KrasG12D activation and selective deletion of IL-17RA in the epithelial vs. immune component using either genetic manipulation or bone marrow transplantation. Deletion of IL17RA from the pancreatic epithelial compartment delayed premalignant lesion development …

Unveiling Immune Checkpoint Therapy Resistance Mechanisms In The Tumor Microenvironment Using High-Dimensional Analyses, Swetha Anandhan

Dissertations & Theses (Open Access)

The advent of immune checkpoint therapy (ICT) has transformed cancer treatment, but its effectiveness is limited in certain cancers like pancreatic ductal adenocarcinoma (PDAC), which exhibit resistance to this therapy. To overcome this challenge, it is crucial to understand the underlying mechanisms that determine tumor response to ICT and develop rational therapeutic combinations. The tumor microenvironment (TME), including suppressive myeloid cells, regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs), plays a pivotal role in ICT responses. Leveraging single-cell technologies, this study explores the role and function of immune subsets in the TME that induce therapy resistance.

Using single-cell RNA sequencing …

Investigating The Distinct Role Of Pd-L2 In Modulating Human T Cells Responses, Anupallavi Srinivasamani

Dissertations & Theses (Open Access)

INVESTIGATING THE DISTINCT ROLE OF PD-L2 IN MODULATING HUMAN T CELL RESPONSES

Anupallavi Srinivasamani, M.S.

Advisory Professor: Michael A. Curran, Ph.D.

Therapeutic blockade of the Programmed cell death-1 (PD-1) receptor and its ligand Programmed death ligand-1 (PD-L1) has revolutionized the treatment of multiple cancers and made durable tumor regression a possibility in the clinic. PD-1 blockade prolonged progression-free survival and overall survival with lesser high-grade toxicity in patients with advanced melanoma when compared to the other FDA-approved checkpoint blockade target, CTLA-4. Unlike CTLA-4, PD-1 is unique in its ability to regulate T cell functions in lymphoid tissues as well as …

Identifying Functional Enhancers For Fibrotic Gene Regulation In Liver Fibrosis, Parnaz Merikhian

Dissertations & Theses (Open Access)

Liver fibrosis is characterized by progressive activation of proliferating and migrating myofibroblasts that lead to accumulation of extracellular matrix (ECM). These myofibroblasts most arise from activated liver-resident hepatic stellate cells (HSCs). There is an increasing number of patients suffering from liver fibrosis in developed countries including the United States, which is anticipated to continue to grow during 2023-2033 period. TGF-β1 is a key cytokine with a significant role in regulating cell differentiation and adhesion in liver fibrosis. TGF-β signaling triggers gene expression changes in HSCs, including that of fibrotic and EMT-related genes, which then functionally promote HSCs activation and fibrogenesis. …

Preclinical Evaluation Of Immunomodulatory Effects Of Aurora Kinase Inhibition In Human Papillomavirus Positive Cancers, Pragya Sinha

Dissertations & Theses (Open Access)

Human papillomavirus (HPV) is the causative agent of cervical cancer and some cancers of the penis, vulva, vagina, anus, and oropharynx. Current therapies for these cancers include a combination of surgery, radiotherapy, and chemotherapy that often results in permanent, life altering adverse effects. Immunotherapy is partially effective, but with significant recurrence and lower long-term survival. Importantly, there are no few biomarker-selective targeted therapies for these cancers. To address this unmet need, our collaborators conducted a large-scale drug screen and identified Aurora Kinase (AK) inhibitors as a unique class of reagents to induce selective apoptosis in HPV+, but not HPV- human …

Functions Of The Trna Splicing Endonuclease And Other Adventures In Rna Processing, Jennifer Hurtig, Ambro Van Hoof

Dissertations & Theses (Open Access)

The tRNA splicing endonuclease (TSEN), has been studied for over three decades for its function in tRNA splicing. However, this enzyme has other functions that are just beginning to be characterized. Mutations in TSEN cause the neuronal disease pontocerebellar hypoplasia (PCH) that is characterized by atrophy of the cerebellum and pons, overall developmental failure, and usually results in death before adolescence. How mutations in TSEN cause these neuronal defects and disease is not understood. In yeast, TSEN has another essential function that is independent of tRNA splicing and is still unknown. In this thesis I strived to understand the other …

Investigating The Roles Of Lung Epithelial Stat3 In Therapeutically Inducible Resistance To Acute Bacterial Pneumonia., Vikram V. Kulkarni, Vikram V. Kulkarni

Dissertations & Theses (Open Access)

Investigating the roles of lung epithelial STAT3 in therapeutically inducible resistance to acute bacterial pneumonia.

Vikram Vitthal Kulkarni, M.S.

Advisory Professor: Scott Evans, MD.

The lung epithelium is a dynamic tissue capable of displaying structural and functional plasticity in response to pathogenic challenges. Our lab has demonstrated that it is possible to therapeutically exploit the lung epithelium’s versatility by inducing resistance to lethal pneumonias caused by viruses, bacteria and fungi. An inhaled combination of a TLR2/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonia caused by Pseudomonas aeruginosa. Pam2ODN-mediated protection requires key signaling …

P120-Catenin Subfamily Members Have Distinct As Well As Shared Effects On Dendrite Morphology During Neuron Development In Vitro, Maxsam Donta

Dissertations & Theses (Open Access)

Proper dendrite morphology is essential for neuronal connectivity and function, and abnormal dendrite morphology is seen in many neurological pathologies. This study characterizes and compares the effects of a group of four proteins – the p120-catenin subfamily – that regulate cytoskeletal remodeling and dendrite morphology. To do this, I tracked the endogenous localization of each p120-subfamily catenin during neuron development, and I determined how altering the expression of each p120-subfamily catenin affects dendrite morphology. I find that all catenins are expressed in dendritic processes and the soma, ARVCF-catenin is expressed at relatively high proportions in the nucleus, and p120-catenin and …

Regulation Of De Novo And Maintenance Dna Methylation By Dnmt3a And Dnmt3b, Yang Zeng

Dissertations & Theses (Open Access)

DNA methylation (5-methylcytosine, 5mC) is essential for the regulation of gene expression and integrity of the mammalian genome. It occurs predominantly in the context of CpG dinucleotides to form a symmetrical pattern on both DNA strands, which allows DNA methylation patterns to be semi-conservatively maintained during DNA replication. There are two classes of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B function primarily as de novo methyltransferases that establish DNA methylation patterns, whereas DNMT1 is the major enzyme responsible for maintaining DNA methylation patterns by converting hemi-methylated CpGs to fully methylated CpGs during DNA replication. Two accessory factors also play critical regulatory …

Prenatal Screening Decision-Making Facilitated Through An Online Patient Education Module, Erin Atkinson

Dissertations & Theses (Open Access)

As recommendations for prenatal genetic screening are expanded to include patients with pregnancies at low risk for aneuploidy, there is a need to develop accessible mechanisms to promote informed decision-making about genetic screening. The use of patient decision aids has been shown to promote informed decision-making. UTHealth Houston has developed and implemented an online module for pre-test triage for genetic counseling and education of low-risk pregnant patients about genetic screening, called the Prenatal Genetic Education Program (PGEP).

Here, through a retrospective chart review, we characterize the use of PGEP to triage previously presumed low-risk patients to genetic counseling, and whether …

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

Dissertations & 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 …

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

Dissertations & 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 …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad

Dissertations & Theses (Open Access)

Missense mutations in the DNA binding domain of the Trp53 gene are characterized as structural (p53R172H) or contact (p53R245W) mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities such as increased metastatic incidence as compared to p53 loss, often mediated by their interaction with a repertoire of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which these mutations drive osteosarcoma progression, we created a mouse model, wherein either the p53 structural mutant p53R172H, or the contact mutant, p53R245W, are expressed specifically in …

Regulation And Function Of Zeb1 Acetylation In Lung Adenocarcinoma Progression And Metastasis, Mabel Perez-Oquendo

Dissertations & Theses (Open Access)

Lung cancer metastasis is leading the causes of cancer-related mortality in the United States and worldwide. Epithelial-to-mesenchymal transition (EMT) is a model for metastasis that results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. Zinc finger E-box-binding homeobox 1 (ZEB1) recognizes and binds to E-boxes of epithelial gene promoters to repress its transcription. ZEB1 has inconsistent molecular weights, which have been attributed to post-translational modifications (PTMs). In the presented dissertation, I specifically addressed the gap in the molecular mechanisms by which PTMs of ZEB1 regulate its ability to induce EMT and how its activity might …

Deephtlv: A Deep Learning Framework For Detecting Human T-Lymphotrophic Virus 1 Integration Sites, Johnathan Jia, Johnathan Jia

Dissertations & Theses (Open Access)

In the 1980s, researchers found the first human oncogenic retrovirus called human T-lymphotrophic virus type 1 (HTLV-1). Since then, HTLV-1 has been identified as the causative agent behind several diseases such as adult T-cell leukemia/lymphoma (ATL) and a HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). As part of its normal replication cycle, the genome is converted into DNA and integrated into the genome. With several hundreds to thousands of unique viral integration sites (VISs) distributed with indeterminate preference throughout the genome, detection of HTLV-1 VISs is a challenging task. Experimental studies typically use molecular biology …