Digital Commons Network^™

Modulation Of Lymphocyte Potassium Channel Kv13 By Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin, Seow Theng Ong, Saumya Bajaj, Mark R Tanner, Shih Chieh Chang, Bankala Krishnarjuna, Xuan Rui Ng, Rodrigo A V Morales, Ming Wei Chen, Dahai Luo, Dharmeshkumar Patel, Sabina Yasmin, Jeremy Jun Heng Ng, Zhong Zhuang, Hai M Nguyen, Abbas El Sahili, Julien Lescar, Rahul Patil, Susan A Charman, Edward G Robins, Julian L Goggi, Peng Wen Tan, Pragalath Sadasivam, Boominathan Ramasamy, Siddana V Hartimath, Vikas Dhawan, Janna Bednenko, Paul Colussi, Heike Wulff, Michael W Pennington, Serdar Kuyucak, Raymond S Norton, Christine Beeton, K George Chandy

Faculty, Staff and Students Publications

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated KV1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to KV1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for KV1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with 18F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat …

Targeting Pd-L1 In Non-Small Cell Lung Cancer Using Car T Cells, Ming Liu, Xu Wang, Wei Li, Xinfang Yu, Pedro Flores-Villanueva, Zijun Y Xu-Monette, Ling Li, Mingzhi Zhang, Ken H Young, Xiaodong Ma, Yong Li

Faculty, Staff and Students Publications

Antibodies against programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the landscape of therapies for non-small cell lung carcinoma (NSCLC); however, the majority of patients do not respond to these agents. In addition, hyperprogressive disease (HPD) develops in a larger portion of NSCLC patients treated with PD-1/PD-L1 inhibitors than in patients treated with standard chemotherapy. The use of chimeric antigen receptor (CAR) T cells has been successful to treat blood cancers but not for solid tumors like NSCLC. In this work, we constructed CAR T cells that target PD-L1 and evaluated their efficacy in NSCLC …

Dendritic Cell Derived Exosomes Loaded With Immunoregulatory Cargo Reprogram Local Immune Responses And Inhibit Degenerative Bone Disease In Vivo, Mahmoud Elashiry, Mohamed M Elashiry, Ranya Elsayed, Mythily Rajendran, Carol Auersvald, Rana Zeitoun, Mohammad H Rashid, Roxan Ara, Mohamed M Meghil, Yutao Liu, Ali S Arbab, Roger M Arce, Mark Hamrick, Mohammed Elsalanty, Marshall Brendan, Rafal Pacholczyk, Christopher W Cutler

Faculty, Staff and Student Publications

Chronic bone degenerative diseases represent a major threat to the health and well-being of the population, particularly those with advanced age. This study isolated exosomes (EXO), natural nano-particles, from dendritic cells, the "directors" of the immune response, to examine the immunobiology of DC EXO in mice, and their ability to reprogram immune cells responsible for experimental alveolar bone loss

Metabolism Of Jq1, An Inhibitor Of Bromodomain And Extra Terminal Bromodomain Proteins, In Human And Mouse Liver Microsomes†, Feng Li, Kevin R Mackenzie, Prashi Jain, Conrad Santini, Damian W Young, Martin M Matzuk

Faculty, Staff and Students Publications

JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male contraceptive target. Although JQ1 possesses favourable physical properties, it exhibits a short half-life. Because the details of xenobiotic metabolism play important roles in the optimization of drug candidates and in determining the role of metabolism in drug efficacy, we investigated the metabolism of JQ1 in human and mouse liver microsomes. …

A Global Slc7a7 Knockout Mouse Model Demonstrates Characteristic Phenotypes Of Human Lysinuric Protein Intolerance, Bridget M Stroup, Ronit Marom, Xiaohui Li, Chih-Wei Hsu, Cheng-Yen Chang, Luan D Truong, Brian Dawson, Ingo Grafe, Yuqing Chen, Ming-Ming Jiang, Denise Lanza, Jennie Rose Green, Qin Sun, J P Barrish, Safa Ani, Audrey E Christiansen, John R Seavitt, Mary E Dickinson, Farrah Kheradmand, Jason D Heaney, Brendan Lee, Lindsay C Burrage

Faculty, Staff and Students Publications

Lysinuric protein intolerance (LPI) is an inborn error of cationic amino acid (arginine, lysine, ornithine) transport caused by biallelic pathogenic variants in SLC7A7, which encodes the light subunit of the y+LAT1 transporter. Treatments for the complications of LPI, including growth failure, renal disease, pulmonary alveolar proteinosis, autoimmune disorders and osteoporosis, are limited. Given the early lethality of the only published global Slc7a7 knockout mouse model, a viable animal model to investigate global SLC7A7 deficiency is needed. Hence, we generated two mouse models with global Slc7a7 deficiency (Slc7a7em1Lbu/em1Lbu; Slc7a7Lbu/Lbu and Slc7a7em1(IMPC)Bay/em1(IMPC)Bay; Slc7a7Bay/Bay) using CRISPR/Cas9 technology by introducing a deletion of exons …

Molecular Diagnosis Of Intestinal Parasites: Impact On Growth Among Preschool-Age Children In Rural Ecuador, Patricia Bryan

Dissertations and Theses (Open Access)

Background: Gastrointestinal (GI) parasites may have important influences on growth outcomes during early childhood. Previous studies investigating the effects of GI parasites on growth have predominantly used microscopy-based diagnostic methods with low sensitivity. Few accurate epidemiologic data are available on GI parasitic infections among rural Ecuadorian children. To investigate the impact of single and multiple GI parasite infections on growth during early childhood data from a longitudinal birth cohort in Ecuador were analyzed.

Purpose: The aims of this study were to determine the prevalence of GI parasites (soil-transmitted helminths and intestinal protozoa) and to describe associations between GI parasitic infections …

A Qualitative Inquiry Exploring Help-Seeking Behaviors And Resilience Strategies Women With Disabilities Utilize When Experiencing Gender-Based Violence In Rural Communities, Kimberly Ann Aguillard

Dissertations and Theses (Open Access)

Women with disabilities (WWD) are at pronounced risk of experiencing multiple forms of severe and prolonged violence, and they face barriers to accessing help. A multitude of factors associated with disability and rurality may compound the experience of violence, including geographic and social isolation, forcing WWD in rural settings to navigate extremely dangerous situations with limited avenues for accessing help and securing safety. This research explored how women with disabilities experiencing violence while living in rural communities navigate programs and policies, make decisions about seeking and securing help, and build resilience despite experiencing violence. The current study methodology empowers this …

Causal Analysis Theory And Application To Alzheimer’S Disease (Ad) And Heart Failure (Hf), Shudi Li

Dissertations and Theses (Open Access)

Alzheimer's disease (AD) and heart failure (HF) are two complex diseases that are caused by the combination of genetic and epigenetic, environmental and other lifestyle factors. Understanding the relationships between genetic and epigenetic variants and other factors of such complex diseases could assist researchers discover disease mechanisms and develop targeted therapies. Much of the research in genetics/epigenetics studies regarding AD and heart diseases have been focused on association analysis. Many researchers have identified genetic/epigenetics variants and phenotypes that are significantly associated with disease pathology. While most of these studies utilize association analysis as the analytical platform, the signals identified by …

Heat Stress Related Symptoms And Pulmonary Function In Oil Spill Response And Cleanup Workers Following The Deepwater Horizon Disaster, Yiyou Li

Dissertations and Theses (Open Access)

The objective of this study was to estimate the relationship between heat stress and pulmonary function among OSRC workers following the Deepwater Horizon (DWH) disaster. Methods: Pulmonary function test results were analyzed from a cohort of oil spill response and cleanup workers 1-3 years following the DWH disaster (N=5,131). Proxies for heat stress was employed by using information on heat stress-related symptoms as well as a questionnaire on stopping work due to heat reported during a structured telephone enrollment questionnaire. Associations between heat stress proxies and lung function were estimated using multivariable linear models and binomial logistic regression models while …

Heat Stress Related Symptoms And Pulmonary Function In Oil Spill Response And Cleanup Workers Following The Deepwater Horizon Disaster, Yiyao Li

Dissertations and Theses (Open Access)

Objective: The objective of this study was to estimate the relationship between heat stress and pulmonary function among OSRC workers following the Deepwater Horizon (DWH) disaster. Methods: Pulmonary function test results were analyzed from a cohort of oil spill response and cleanup workers 1-3 years following the DWH disaster (N=5,131). Proxies for heat stress was employed by using information on heat stress-related symptoms as well as a questionnaire on stopping work due to heat reported during a structured telephone enrollment questionnaire. Associations between heat stress proxies and lung function were estimated using multivariable linear models and binomial logistic regression models …

Area-Level Landfill Density And Asthma Prevalence In Urban Texas Areas, Jessica Meighan Herrin

Dissertations and Theses (Open Access)

Environmental exposures, especially air pollutants, pose a threat for an increase in asthma prevalence. In particular, hydrogen sulfide (H2S) gas can cause severe health effects closely resembling asthmatic symptoms. Ambient concentrations of H2S gas correlates with the amount of solid waste found in landfills. The potential for adverse health risks associated with H2S emitted from landfills is of concern for those populations living in close proximity to landfills. Asthma is one of the adverse health effects that can occur due to H2S exposure. However, there is a lack of detailed studies characterizing possible associations between the density of landfills and …

Bst2 Isoforms: Distribution And Potential Use In Cancer Therapeutics, Ahmed Muhsin

Dissertations and Theses (Open Access)

Identifying a cancer-specific cellular target is one of the key factors that can pave a “bench to the bedside” path of a target therapy. Bone marrow stromal cell antigen 2 (BST2) is a raft-associated type II transmembrane protein with an unusual topology. Analyses showed a variable degree of BST2 expression in most organs. Two research groups identified different BST2 isoforms of BST2 generated by posttranscriptional modification. In this research, I studied the long BST2 isoform’s distribution in breast tissue and B cell lines using the novel monoclonal antibody (MAb) LA5, an anti-BST2-long MAb. This approach revealed the expression of the …

Identification Of Trim24 Domain Essentiality In Primary Trim24coe Carcinosarcoma Cell Lines, Cem Dede

Dissertations and Theses (Open Access)

Regulation of transcriptional control is a critical feature for organismal development and survival. Because of its effects on chromatin-controlled expression, disruptions of this delicately tuned mechanism are an important factor in development of tumorigenesis. Therefore, there is a growing interest in targeting these control mechanisms for their potential therapeutic values.

Our lab previously discovered the epigenetic regulator function of Tripartite motif protein 24 (TRIM24) through its H3K4me0 and H3K23ac dual histone signature reader function, its negative regulatory effect on the p53 tumor suppressor, in addition to its shown oncogenic driving capacity on immortalized mammary epithelial cells when overexpressed. Although TRIM24 …

Aging Lowers Pex5 Levels In Cortical Neurons In Male And Female Mouse Brains, Ndidi-Ese Uzor

Dissertations and Theses (Open Access)

Peroxisomes are small organelles with critical functions: lipid synthesis, breakdown of reactive oxygen species by antioxidant enzymes, and amino acid degradation. In the brain, peroxisomal lipids make up the myelin sheath. Brain peroxisomal dysfunction leads to lipid disruption or neurological consequences if key peroxisomal proteins are absent. Still, it is unclear how peroxisomes are affected in neurodegenerative diseases and in normal brain aging. This work examines peroxisomal markers in three settings: 1) in a neuronal and 2) animal model of Huntington disease (HD), where mutant huntingtin (mHtt), the causative protein in Huntington disease pathogenesis is expressed, and 3) in the …

A Screen For Peptides Targeting Chemoresistant Metastatic Triple-Negative Breast Cancer, Shraddha Subramanian

Dissertations and Theses (Open Access)

Cancer metastasis is the principal cause of most cancer-associated morbidities. While radiotherapy, hormone therapy, and novel therapeutic strategies, including immunotherapy, have shown promise in inhibiting tumor growth, chemotherapy remains the mainstay in the clinical management of metastatic progression. This is often the case in triple-negative breast cancer (TNBC), an aggressive breast cancer subtype where tumorigenesis is independent of HER-2, progesterone, or estrogen receptor expression. Despite improving TNBC prognosis, recent studies report that after chemotherapy administration, TNBC drug-tolerant tumor cell survival, relapse, and metastatic dissemination may be promoted. Overcoming drug resistance exhibited by metastatic tumor cells is a challenge owing to …

Longitudinal Clonal Lineage Dynamics And Functional Characterization Of Pancreatic Cancer Chemo-Resistance And Metastasization, Chieh-Yuan Li

Dissertations and Theses (Open Access)

In recent years, technological advancements, such as next-generation sequencing and single-cell interrogation techniques, have enriched our understanding in tumor heterogeneity. By dissecting tumors and characterizing clonal lineages, we are better understanding the intricacies of tumor evolution. Tumors are represented by the presence of and dynamic interactions amongst clonal lineages. Each lineage and each cell contributes to tumor dynamics through intrinsic and extrinsic mechanisms, and the variable responses of clones to perturbations in the environment, especially therapeutics, underlie disease progression and relapse. Thus, there exists a pressing need to understand the molecular mechanisms that determine the functional heterogeneity of tumor sub-clones …

Artificial Intron Technology To Generate Conditional Knock-Out Mice, Amber N. Thomas-Gordon

Dissertations and Theses (Open Access)

Genetic engineering has been re-shaped by the invention of new tools in modern biotechnology in a way that offers precision and efficiency in modifying the genome at a single nucleotide level and/or allowing precise control of gene expression. Such gene manipulation brings about significant findings and revelations in comprehending more about embryonic development, cellular and physiological functions, and disease pathology. Current methods used to produce conditional knockouts have limitations on conditional allele placement and modification varies among genes in different organisms. Thus, a system for generating conditional alleles with fidelity remains a challenge. My goal was to examine an approach …

Characterization Of Treatment Planning System Photon Beam Modeling Errors In Iroc Houston Phantom Irradiations, Mallory Glenn

Dissertations and Theses (Open Access)

In radiation therapy, proper commissioning of the treatment planning system’s (TPS) dose calculation algorithm is critical because any errors in this process impact all treatment plans prepared in the system. Previously, TPS errors have been identified as a major cause for poor phantom irradiation performance, which may also mean that patients are treated suboptimally. The purpose of this work was to investigate the TPS beam modeling developed by the radiotherapy community to understand where inconsistencies may arise, which variables are most susceptible to variations, and in what way changing these variables can alter dose calculations.

Using the Imaging and Radiation …

Modulating Avidity Of H8f4-Car By Regulation Of Expression Via Codon Modification, Rolando Vedia

Dissertations and Theses (Open Access)

Despite recent advances in the field of cancer immunotherapy and chimeric antigen receptor (CAR) therapies for the treatment of acute myeloid leukemia (AML), there is a need for more unique and innovative modalities to improve these therapies. Our group has extensively studied and demonstrated the potential of targeting the leukemia-associated antigen PR1 in the setting of AML. PR1 is an HLA-A2-restricted nonameric peptide derived from serine proteases neutrophil elastase and proteinase 3, is overexpressed on myeloid leukemia cells, and expressed at normal low levels in healthy hematopoietic cells. We have demonstrated efficacy in targeting PR1/HLA-A2 via the novel development of …

Directed Evolution Of Macrocyclic Peptides For Inhibition Of Autophagy, Joshua Gray

Dissertations and Theses (Open Access)

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B—two essential components of …

Investigating The Role Of Quaking In Antigen Uptake And Cross-Presentation By Dendritic Cells, Yating Li

Dissertations and Theses (Open Access)

Dendritic cells (DCs) are considered the most potent antigen presenting cells (APC) due to their superior capability of cross-presenting exogenous antigens to CD8⁺ T cell for strong adaptive immune responses. They internalize foreign antigens by phagocytosis, endocytosis or macropinocytosis, which are then processed in endosomal compartments and loaded onto MHC Class I molecules. However, the molecular mechanisms regulating exogenous antigen uptake and cross-presentation by DCs are not fully understood.

In this study, we discovered that an RNA-binding protein, Quaking (QKI) plays a pivotal role in antigen uptake by DCs. Our previous studies in neural stem cells and microglia have …

Active Magnetic Radiation Shielding For Long-Duration Human Spaceflight, Kristine Ferrone

Dissertations and Theses (Open Access)

Exploration of interplanetary space presents dramatic hazards to human survival.

Space radiation hazards outside the protection of the Earth’s magnetosphere can

produce both acute and chronic health risks and thus become limiting factors for

NASA’s planned mission to Mars by the 2030s. Radiation exposure on a Mars mission

is delivered primarily by high energy ions from galactic cosmic rays and moderate

energy protons from solar particle events. The chronic radiation dose due to galactic

cosmic rays on a typical Mars mission is on the order of 1 Sv, and additional acute

radiation dose from solar flares can reach over 4 …

Mutations Within And Between Early Cell Division Proteins And Their Effects On Division Regulation In Escherichia Coli, Kara Schoenemann

Dissertations and Theses (Open Access)

Cell division is a highly regulated process that must coordinate multiple implicit activities in different locations in the cell simultaneously. E. coli utilizes a macromolecular machine known as the divisome to accomplish cytokinesis. Assembly of the divisome begins with the assembly of a simpler structure known as the proto-ring. The proto-ring consists mainly of three essential proteins: FtsZ and its membrane tethers FtsA and ZipA. In this work, I aimed to understand the early regulation of division in E. coli by investigating the structure/function relationships of the proto-ring proteins, as well as their interactions with one another and how these …

Targeting Unique Domains Of Lsd1 Regulates Pediatric Glioma Innate Immunity And Nk Cell Metabolism, Cavan Bailey

Dissertations and Theses (Open Access)

Regulation of chromatin accessibility is a key mechanism of cellular identity, allowing different tissues to develop using the same DNA template. Cancers will often hijack these epigenetic pathways, reactivating developmental genes to drive growth and deactivating tumor suppressor and immune recognition genes. Chromatin-modifying proteins deposit and remove chemical moieties from histone tails to aid in governing gene expression, and these proteins have become a new therapeutic target in cancer. Traditional chemotherapeutics aim to damage DNA, dysregulate cell division, or block hormonal growth signals, but epigenetic therapy can target vulnerabilities specific to cancer cells and broadly change gene expression patterns that …

Elevated Cochlear Adenosine Causes Hearing Loss Via Adora2b Signaling, Jeanne Manalo

Dissertations and Theses (Open Access)

Over 538 million people in the world have been diagnosed with hearing loss (HL). Current treatments for the most common type of HL, sensorineural HL, are limited to hearing aids and cochlear implants with no FDA-drugs available. The hearing process demands an abundance of ATP and HL is often attributed to a disruption in this metabolic energy currency. Patients who lack adenosine deaminase (ADA), the enzyme that irreversibly metabolizes adenosine, have high levels of adenosine that yield severe health problems, including HL; however, the pathogenic mechanisms behind HL and adenosine remain elusive. Our lab has found a HL phenotype in …

Methods To Investigate Hyperthermia Induced By Tumor Treating Fields, Ruchi Singh

Dissertations and Theses (Open Access)

Tumor Treating Fields (TTFields) are an antineoplastic treatment delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. TTF’s is a non-invasive application of low-intensity (1-3 V/cm), intermediate-frequency (100-500 kHz) alternating electric fields. The predominant mechanism by which TTFields are thought to kill tumor cells is the disruption of mitosis through the depolymerization of microtubules and interruption of the spindle structure leading to mitotic catastrophe and the formation of non-viable daughter cells. Tumor Treating fields do not stimulate nerves and muscle because of their high frequency, and do …

Putative Roles Of Cd200 In The Leukemogenesis And Immune Evasion Of Leukemia Stem Cells, Shelley Herbrich

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) stem cells (LSC) are capable of surviving current standard chemotherapy and are the likely source of deadly, relapsed disease. While stem cell transplant serves as proof-of-principle that AML LSCs can be eliminated by the immune system, the translation of existing immunotherapies to AML have been met with limited success. Consequently, understanding and exploiting the unique immune mechanisms of AML LSCs is critical. To identify novel immunotherapeutic targets, we sourced multiple large, publicly available datasets and identified CD200 as a potential stem-cell specific immune checkpoint in AML. We hypothesized that CD200 was a stem-cell specific mechanism of …

Histological And Functional Characterization Of Cervical Spinal Cord Injury After Graded Contusion, Chrystine Gallegos

Dissertations and Theses (Open Access)

Most spinal cord injuries (SCIs) are cervical contusions and result in deficits for both locomotion and reaching and grasping functions. Previous studies have characterized histological and functional deficits in locomotion using primarily thoracic contusions, but most patients have cervical injuries. Damage to descending long spinal tracts (dLSTs) is one well-established cause of functional loss after SCI and has been explored in laceration and transection models, but these are not clinically relevant. In this study, I will explore the histological and functional deficits after graded cervical hemicontusion SCI and examine the potential contribution of different histological deficits to forelimb function after …

Statistical Methods For Resolving Intratumor Heterogeneity With Single-Cell Dna Sequencing, Alexander Davis

Dissertations and Theses (Open Access)

Tumor cells have heterogeneous genotypes, which drives progression and treatment resistance. Such genetic intratumor heterogeneity plays a role in the process of clonal evolution that underlies tumor progression and treatment resistance. Single-cell DNA sequencing is a promising experimental method for studying intratumor heterogeneity, but brings unique statistical challenges in interpreting the resulting data. Researchers lack methods to determine whether sufficiently many cells have been sampled from a tumor. In addition, there are no proven computational methods for determining the ploidy of a cell, a necessary step in the determination of copy number. In this work, software for calculating probabilities from …

Symmetric Inverse Consistent Nonlinear Registration Driven By Mutual Information, Wen Fury, Keun Woo Park, Zhuhao Wu, Eunhee Kim, Moon-Sook Woo, Yu Bai, Lynn E Macdonald, Susan D Croll, Sunghee Cho

Faculty, Staff and Student Publications

BACKGROUND AND PURPOSE: Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months.

METHODS: Adult C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Longitudinal transcriptome levels were measured at 10 time points after stroke from acute to recovery phases of ischemic stroke. Localization and the number of mononuclear phagocytes were determined in the postischemic brain. Whole-mount brain …