Life Sciences Commons^™

Using Mouse Models To Define How The P53 R72p Polymorphism Impacts The Adverse Effects Of Doxorubicin And Ionizing Radiation, Emily Dominguez

Dissertations and Theses (Open Access)

The single nucleotide polymorphism (SNP) at codon 72 of the tumor suppressor gene p53 codes for either an arginine (R) or proline (P) (p53 R72P). This SNP may impact how cells respond to genotoxic insult. Studies in cell culture and in tissues from mouse models of the SNP indicate that, in response to gentoxic treatment, the two variants may differentially induce apoptosis and expression of p53 target genes. In epidemiological studies, the P variant is associated with decreased cancer survival and increased risk of side-effects from genotoxic cancer treatment. Genotoxic therapy is still the mainstay of cancer treatment, and doxorubicin …

The Role Of Streptococcus Gallolyticus Subspecies Gallolyticus In Colon Cancer Development, Jennifer L. Herold

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer in men and women and is also the third most common cause of cancer death. A large body of evidence points towards the possibility that bacteria can have a significant impact on the development of cancer. It has been suggested that Streptococcus gallolyticus subsp. gallolyticus, a group D streptococci, may play a role in the development of CRC. Sg, formerly S. bovis biotype I, has been shown to be highly associated with CRC. In observing patients with either Sg bacteremia or endocarditis it was found that 25-80% of …

Concomitant Targeting Of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets Of Non-Small Cell Lung Cancer, Dennis Ruder

Dissertations and Theses (Open Access)

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, …

Maguk Scaffolds Organize A Key Synaptic Complex In Horizontal Cell Processes Contacting Photoreceptors, Alejandro Vila, Ph.D.

Dissertations and Theses (Open Access)

Synaptic processes and plasticity of synapses are mediated by large suites of proteins. In most cases, many of these proteins are tethered together by synaptic scaffold proteins. Scaffold proteins have a large number and typically a variety of protein interaction domains that allow many different proteins to be assembled into functional complexes. As each scaffold protein has a different set of protein interaction domains and a unique set of interacting partners, the presence of synaptic scaffolds can provide insight into the molecular mechanisms that regulate synaptic processes. In studies of rabbit retina, we found SAP102 and Chapsyn110 selectively localized in …

The Role Of Phosphorylation In Pam2 Motif-Containing Proteins Mediated Messenger Rna Deadenylation, Kai-Lieh Huang

Dissertations and Theses (Open Access)

Phosphorylation regulates many cellular processes. However, its role in mRNA deadenylation, a process to remove poly adenosines from the mature mRNA 3’ end tail, is unclear. The length of poly(A) tail determines mRNA stability and translation efficiency. Poly(A)-binding protein (PABP), which binds to newly synthesized poly(A) tails homogeneously and is known as a scaffold protein for PAM2 motif-containing proteins, plays a pivotal role in the shortening of poly (A) tails. This study is to examine the role of phosphorylation of PAM2 motif–containing proteins in regulating their interactions with PABP and mRNA deadenylation function.

The PAM2 motif, a region required for …

Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang

Dissertations and Theses (Open Access)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce …

Targeting Pd-1/Pdl-1 Signaling In The Treatment Of Osteosarcoma Lung Metastasis, Pooja Dhupkar 3012359

Dissertations and Theses (Open Access)

Osteosarcoma (OS) manifests itself as pulmonary metastasis, which is a major cause of death in OS patients. Novel treatments like immunotherapy hold promise for the treatment of OS pulmonary metastasis. However, immunosuppressive mechanisms such as binding of immune inhibitory receptor, PD-1 with PDL-1, which is upregulated in cancer cells, may cause disease relapse.

The effect of PD-1 blockade on NK cells and macrophages has not been investigated till date. The aim of this study was to determine if PD-1 blockade leads to of OS lung metastasis regression and study the role of NK cells and/or macrophages in the anti-PD-1 responses. …

Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang

Dissertations and Theses (Open Access)

Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important …

Cellular And Genetic Bases Of Cold Nociception And Nociceptive Sensitization In Drosophila Larvae, Heather N. Turner

Dissertations and Theses (Open Access)

Organisms from flies to mammals utilize thermoreceptors to detect and respond to noxious thermal stimuli. Although much is understood about noxious heat avoidance, our understanding of the basic biology of noxious cold perception is gravely minimal. Numerous clinical conditions disrupt the sensory machinery, such as in patients suffering from tissue damage (from wound or sunburn), or injury to the peripheral nerves, as in patients with diabetes or undergoing chemotherapy. Our goal is to determine the genetic basis for noxious cold perception and injury-induced nociceptive sensitization using the genetically tractable Drosophila model. Using a novel "cold probe" tool and assay we …

Role Of Phosphorylation In The Regulation Of Prmt5, Alexsandra B. Espejo

Dissertations and Theses (Open Access)

PRMT5 is a member of a group of proteins that mediate arginine methylation. It is involved in diverse cellular processes, including cell differentiation, splicing, transcription elongation and epigenetic silencing, and its expression is dysregulated in many cancers. Due to its pleiotropic functions, PRMT5 is subject to multi-level regulation. Post-translational modification (PTM) of proteins can modulate an array of cellular processes by regulating both protein interactions and protein structural changes. PRMT5 is commonly found associated with other proteins; these interactions seem to control both its catalytic activity and its substrate specificity. Recently, it became clear that PRMT5 is phosphorylated at a …

Datagauge: A Model-Driven Framework For Systematically Assessing The Quality Of Clinical Data For Secondary Use, Jose Franck Diazvasquez

Dissertations and Theses (Open Access)

There is growing interest in the reuse of clinical data for research and clinical healthcare quality improvement. However, direct analysis of clinical data sets can yield misleading results. Data Cleaning is often employed as a means to detect and fix data issues during analysis but this approach lacks of systematicity. Data Quality (DQ) assessments are a more thorough way of spotting threats to the validity of analytical results stemming from data repurposing. This is because DQ assessments aim to evaluate ‘fitness for purpose’. However, there is currently no systematic method to assess DQ for the secondary analysis of clinical data. …

Circumventing Cisplatin Resistance In Ovarian Cancers Through Reactivation Of P53 By Non-Cross-Resistant Platinum Analogs, Michelle Martinez-Rivera

Dissertations and Theses (Open Access)

Abstract

CIRCUMVENTING CISPLATIN RESISTANCE IN OVARIAN CANCERS THROUGH REACTIVATION OF P53 BY NON-CROSS-RESISTANT PLATINUM ANALOGS

Michelle Martinez-Rivera, B.S.

Advisory Professor: Zahid H. Siddik, Ph.D.

Cisplatin (cis-Pt), an anticancer platinum (Pt) drug, is used widely in the treatment of several malignancies, such as ovarian cancer. This Pt compound induces DNA damage, which results in p53 activation through post-translational modifications, mainly phosphorylation, culminating in execution of programmed cell-death. However, despite initial therapeutic response to cis-Pt, clinical resistance to this drug emerges leading to disease progression. Pt-resistance phenotypes have been associated with dysfunction in the p53 signaling pathway. Therefore, an effort to understand …

Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang

Dissertations and Theses (Open Access)

14-3-3ζ is a ubiquitously expressed family member of proteins that have been implicated to have oncogenic potential through its interactions and involvement in cancer initiation and progression. 14-3-3ζ belongs to the highly conserved 14-3-3ζ protein family and modulates numerous pathways in cancer. Overexpression of 14-3-3ζ is an early event, occurs in more than 40% of human breast cancer cases, and is associated with disease recurrence and poor prognosis. Metabolic reprogramming is a hallmark of cancer. Cancer cells elevate aerobic glycolysis to produce metabolic intermediates and reducing equivalents, thereby facilitating cellular adaptation to the adverse environment and sustaining fast proliferation. Interestingly, …

The Impact Of Cortical State On Neural Coding And Behavior, Charles Beaman

Dissertations and Theses (Open Access)

The brain is never truly silent – up to 80% of its energy budget is expended during ongoing activity in the absence of sensory input. Previous research has shown that sensory neurons are not exclusively influenced by external stimuli but rather reflect interactions between sensory inputs and the ongoing activity of the brain. Yet, whether fluctuations in the state of cortical networks influence sensory coding in neural circuits and the behavior of the animal are unknown. To shed light on this issue, we conducted multi-unit electrophysiology experiments in visual areas V1 and V4 of behaving monkeys. First, we studied the …

Development Of An In Silico Kir Genotyping Algorithm And Its Application To Population And Cancer Immunogenetic Analyses, Howard Rosoff

Dissertations and Theses (Open Access)

Gene content determination and variant calling in the complex KIR genomic region are useful for immune system function analysis, pathogenesis and disease risk factor elucidation, immunotherapy development, evolutionary investigations, and human migration modeling. Sequence-specific oligonucleotide and sequence-specific primer PCR methods are the de facto standards for KIR presence/absence identification, but the current platforms are unsuitable for SNP calling, impractical for KIR typing large cohorts of DNA samples, and inapplicable for typing repositories in which sequence data, but not cells or cell analytes, are available. Alternative typing methods, such as in silico sequence-based typing, can address the problems associated with amplicon-based …

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

Dissertations and Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found …

Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li

Dissertations and Theses (Open Access)

Molecular profiling has identified 5 distinct subtypes of breast cancer, luminal A, luminal B, HER2-enriched, basal-like, and claudin-low breast cancer. These 5 subtypes correlate with hormone response, patient prognosis, and response to therapy. Although steady state gene expression patterns have been explored using expression microarrays, very little is known about the initial, disease-driving transcriptional changes in these cancers or epigenetic changes associated with the differential gene expression signatures. Defining these changes may provide new insights into the mechanisms by which these subtypes arise, as well as new avenues for breast cancer prevention, diagnosis, and treatment. Using Chromatin Immunoprecipitation sequencing and …

Interrogating Dux4 Mrna 3′ End Processing, Natoya J. Peart

Dissertations and Theses (Open Access)

Double Homeobox 4, Dux4, is the leading candidate gene for Facioscapulohumeral Dystrophy (FSHD). FSHD is the third most common muscular dystrophy, and is characterized by progressive muscle weakness primarily in the upper body. In individuals diagnosed with FSHD, Dux4 is inappropriately expressed in somatic cells due to two conditions. The first is hypomethylation of the subtelomeric D4Z4 repeats on chromosome 4. Each D4Z4 repeat on chromosome 4 is 3.3kb in length and contains the open reading frame for Dux4. Hypomethylation of the D4Z4 repeats primarily occurs due to contraction of the repeats from 11-100 (typical numbers in the healthy population) …

Tnf Signaling During Tissue Damage-Induced Nociceptive Sensitization In Drosophila, Juyeon Jo

Dissertations and Theses (Open Access)

Tumor necrosis factor (TNF) signaling is required for inflammatory nociceptive sensitization in both Drosophila and vertebrates. In Drosophila larval model of nociceptive sensitization, UV irradiation in results in epidermal apoptosis and thermal allodynia. TNF/Eiger is produced from dying epidermal cells and acts its receptor in nociceptive sensory neurons to induce thermal allodynia. Inhibition of TNF signaling results in attenuation of nociceptive sensitization whereas epidermal apoptosis still occurs in the absence of TNF. Major gaps in this model are the precise relationship between apoptotic cell death and production of TNF/Eiger, downstream signaling mediators for TNFR/Wengen, and target genes that alter nociceptive …

Defining The Functions Of Usp22 And Usp44 In Regulation Of H2bub1 Levels, Xianjiang Lan

Dissertations and Theses (Open Access)

Aberrant levels of histone ubiquitination are involved in various human diseases including neurodegenerative disorders and cancers. Particularly, Histone H2B monoubiquitination (H2Bub1) is highly associated with gene regulation in both normal cells and diseases. Many deubiquitinases (mainly USPs) are defined to regulate global H2Bub1 levels. However, how these USPs are regulated and how they contribute to diseases are not well understood.

USP22, part of the deubiquitination module (DUBm) in the SAGA complex, is a well-defined regulator of H2Bub1 levels. ATXN7, another crucial subunit of the SAGA DUBm, is involved in a neurodegenerative disease, spinocerebellar ataxia type 7 (SCA7), due to a …

Function And Mechanism Of Alkbh5 In N6-Methyl-Adenosine Rna Modification In Glioblastoma, Sicong Zhang

Dissertations and Theses (Open Access)

N⁶-methyl-adenosine (m⁶A) is the most prevalent internal chemical modification of mRNAs in eukaryotes. In mammals, m⁶A installed by m⁶A methyltransferases METTL3 and METTL14 is erased by two members of the AlkB family of nonheme Fe(II)/a-ketoglutarate (a-KG)-dependent dioxygenases, fat-mass and obesity associated protein (FTO) or ALKBH5. ALKBH5 affects nuclear RNA export and metabolism, gene expression and mouse fertility. To date, little is known about the biological significance of m⁶A in human cancer. We found that ALKBH5 is highly expressed in human glioblastoma stem cells which are resistant to conventional therapy and …

Novel Mechanisms Of Β-Adrenergic Signaling In Prostate Cancer Progression, Mohit Hulsurkar

Dissertations and Theses (Open Access)

Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.

Recently, it has been found that activation of β-adrenergic signaling pathway …

Implications Of Computational Cognitive Models For Information Retrieval, Joshua Caleb Goodwin

Dissertations and Theses (Open Access)

This dissertation explores the implications of computational cognitive modeling for information retrieval. The parallel between information retrieval and human memory is that the goal of an information retrieval system is to find the set of documents most relevant to the query whereas the goal for the human memory system is to access the relevance of items stored in memory given a memory probe (Steyvers & Griffiths, 2010).

The two major topics of this dissertation are desirability and information scent. Desirability is the context independent probability of an item receiving attention (Recker & Pitkow, 1996). Desirability has been widely utilized in …

Regulation Of The Escrt Function Of Alix, Sheng Sun

Dissertations and Theses (Open Access)

The ESCRT (endosomal sorting complex required for transport) is an evolutionary conserved membrane remodeling machinery that performs membrane invagination and abscission. ALIX is a widely expressed adaptor protein that is critically involved in three classical ESCRT-mediated processes, including MVB (multivesicular body) sorting, cytokinetic abscission and retroviral budding. Previous studies have demonstrated that ALIX involvement in these ESCRT-mediated processes requires ALIX interaction with the ESCRT-III component CHMP4 as well as a cargo protein. However, the native form of ALIX contains a default intramolecular interaction between N-terminal Bro1 domain and C-terminal PRD (proline-rich domain), leading to a closed conformation of ALIX that …

Lipocalin 2 Promotes The Establishment Of A Pro-Tumorigenic Microenvironment In Pancreatic Cancer, Sobeyda B. Gomez-Chou

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by a dismal prognosis with a 5-year survival rate of 7%. A unique hallmark of this disease is an abundant desmoplastic reaction that can account for up to 90% of the solid tumor volume. Key components of the PDAC stroma include the extracellular matrix (ECM) rich in collagen type I and III, activated pancreatic stellate cells (PSCs) and inflammatory cells such as neutrophils and macrophages. The main line of evidence has suggested a pro-tumorigenic role for the PDAC stroma as it has been shown to help enhance tumor growth, invasive potential and …

Ethnic Identity And Teratogenic Risk Perceptions, Katie M. Chan

Dissertations and Theses (Open Access)

Elevated perceptions of teratogenic risk can cause anxiety and confusion among pregnant women. To assess whether ethnic identity and demographic factors can influence teratogenic risk perceptions, 194 pregnant women in Houston were surveyed using the Multigroup Ethnic Identity Measure (MEIM) and visual analog scales to quantify perceptions of teratogenic risk for common exposures during pregnancy. Overall, participants estimated an elevated baseline risk of 25% for birth defects among the general population. In addition, participants overestimated birth defect risks for specific exposures, such as alcohol and marijuana. Based on the MEIM scores, ethnic identity was not significantly associated with teratogenic risk …

Genomic Drivers Of Cutaneous Squamous Cell Carcinoma Development, Vida Chitsazzadeh

Dissertations and Theses (Open Access)

Skin cancer is the most common malignancy in humans. Annually, in U.S. there are over 3 million cases with an estimated overall economic impact of $2 billion. Cutaneous Squamous Cell Carcinoma (cuSCC) comprises 15-20% of all skin cancers. cuSCC has the best-defined progression from a distinct precancerous lesion, the Actinic Keratosis (AK), to invasive cuSCC. Destructive therapies for AK treatment must be used repetitively, causing significant morbidity. There is a tremendous need for targeted diagnostics and therapy for AKs, representing an important opportunity for secondary skin cancer prevention. Our knowledge of the molecular and cellular events that lead to the …

Insights Into Determinants That Contribute To Colonization, Virulence And Antibiotic Resistance In Enterococci, Maria Camila Montealegre

Dissertations and Theses (Open Access)

Enterococcus faecalis and Enterococcus faecium are increasingly common as causative agents of human infections, many of which are very difficult to treat due to multi-drug resistance. The work presented in the first part of this dissertation elucidates a mechanism for the regulation of pilus expression. I showed that ATT is the initiation codon of ebpA, the first gene of an operon that codes for the endocarditis and biofilm-associated pili (Ebp), a recognized virulence factor in E. faecalis. The presence of this rare start codon downregulates EbpA translation and protein levels, diminishing biofilm and binding abilities of …

Developing And Using Methyl-Specific Antibodies To Study The Biological Roles Of Arginine Methylation, Vidyasiri Vemulapalli

Dissertations and Theses (Open Access)

Arginine residues can be modified in three different ways to produce asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and monomethylarginine (MMA). These modifications are catalyzed by a family of nine protein arginine methyltransferases (PRMT1-9), which are of three types (I, II, and III). The majority of Type I enzymes asymmetrically dimethylate Glycine- and Arginine-rich (GAR) motifs, except for PRMT4, which methylates Proline-, Glycine-, and Methionine-rich (PGM) motifs. The same substrates (GAR or PGM motifs) can also be dimethylated by PRMT5 in a symmetric fashion. However, it is not clear whether there are dedicated residues within these motifs for ADMA and SDMA, …

Network Dynamics Of Visual Object Recognition, Mehmet C. Kadipasaoglu

Dissertations and Theses (Open Access)

Visual object recognition is the principal mechanism by which humans and many animals interpret their surroundings. Despite the complexity of neural computation required, object recognition is achieved with such rapidity and accuracy that it appears to us almost effortless. Extensive human and non-human primate research has identified putative category-selective regions within higher-level visual cortex, which are thought to mediate object recognition. Despite decades of study, however, the functional organization and network dynamics within these regions remain poorly understood, due to a lack of appropriate animal models as well as the spatiotemporal limitations of current non-invasive human neuroimaging techniques (e.g. fMRI, …