Cell and Developmental Biology Commons^™

Genome Engineering: Drosophila Melanogaster And Beyond, Kjt Venken, A Sarrion-Perdigones, Pj Vandeventer, Ns Abel, Ae Christiansen, Kl Hoffman

Faculty, Staff and Students Publications

A central challenge in investigating biological phenomena is the development of techniques to modify genomic DNA with nucleotide precision that can be transmitted through the germ line. Recent years have brought a boon in these technologies, now collectively known as genome engineering. Defined genomic manipulations at the nucleotide level enable a variety of reverse engineering paradigms, providing new opportunities to interrogate diverse biological functions. These genetic modifications include controlled removal, insertion, and substitution of genetic fragments, both small and large. Small fragments up to a few kilobases (e.g., single nucleotide mutations, small deletions, or gene tagging at single or multiple …

Eosinophilic Esophagitis In Children And Its Relationship With Parental Allergies: Texas Children's Hospital Experience, G Hiremath, D Byramji, A Pacheco, G Constantine, C Davis, R Shulman, A Olive

Faculty, Staff and Students Publications

BACKGROUND: Eosinophilic esophagitis (EoE) is an allergen-mediated, clinicopathological condition affecting all ages. The characteristics of children with EoE in the southwestern USA have not been fully described. Furthermore, very little is known about the relationship between parental allergies and risk of EoE in their offspring in this patient population. AIMS: To characterize children with EoE and to examine the relationship between prevalence of parental allergies and occurrence of EoE in their offspring at a single referral pediatric center in the southwestern USA. METHODS: Demographic and clinical information of 126 children (=18 years of age) with EoE was abstracted in a …

Efficacy Of Psychosocial Interventions In Inducing And Maintaining Alcohol Abstinence In Patients With Chronic Liver Disease: A Systematic Review, A Khan, A Tansel, Dl White, Wt Kayani, Wt Bano, J Lindsay, Hb El-Serag, F Kanwal

Faculty, Staff and Students Publications

BACKGROUND & AIMS: We conducted a systematic review of efficacy of psychosocial interventions in inducing or maintaining alcohol abstinence in patients with chronic liver disease (CLD) and alcohol use disorder (AUD). METHODS: We performed structured keyword searches in PubMed, PsychINFO, and MEDLINE for original research articles that were published from January 1983 through November 2014 that evaluated the use of psychosocial interventions to induce or maintain alcohol abstinence in patients with CLD and AUD. RESULTS: We identified 13 eligible studies that comprised 1945 patients; 5 were randomized controlled trials (RCTs). Delivered therapies included motivational enhancement therapy, cognitive behavioral therapy (CBT), …

Glial Contributions To Neural Function And Disease, Mn Rasband

Faculty, Staff and Students Publications

The nervous system consists of neurons and glial cells. Neurons generate and propagate electrical and chemical signals, whereas glia function mainly to modulate neuron function and signaling. Just as there are many different kinds of neurons with different roles, there are also many types of glia that perform diverse functions. For example, glia make myelin; modulate synapse formation, function, and elimination; regulate blood flow and metabolism; and maintain ionic and water homeostasis to name only a few. Although proteomic approaches have been used extensively to understand neurons, the same cannot be said for glia. Importantly, like neurons, glial cells have …

Early Rescue Of Interneuron Disease Trajectory In Developmental Epilepsies, Ms Siehr, Jl Noebels

Faculty, Staff and Students Publications

The discovery of over 150 monogenic epilepsies and advances in early genetic diagnoses have launched a search for molecular strategies and developmental timetables to reverse or even prevent the course of these debilitating brain disorders. Orthologous rodent models of key disease genes are providing important examples of the range of targets, and serve as valuable test systems for perinatal therapeutic approaches. While gene-specific analyses of single rare 'orphan' diseases are each narrow in scope, they illuminate downstream pathways converging onto interneurons, and treatments that strengthen inhibition during cortical maturation may provide broad protection against these seemingly disparate gene errors. Several …

Effect Of Two-Year Caloric Restriction On Bone Metabolism And Bone Mineral Density In Non-Obese Younger Adults: A Randomized Clinical Trial, Dt Villareal, L Fontana, Sk Das, Et Al.

Faculty, Staff and Students Publications

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two-hundred eighteen non-obese (body mass index [BMI] 25.1?±?1.7?kg/m(2) ), younger (age 37.9?±?7.2 years) adults were randomly assigned to 25% CR (CR group, n?=?143) or ad libitum (AL group, n?=?75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone-active hormones, nutrient intake, and physical activity. Body weight (-7.5?±?0.4 versus …

Local Corticotropin Releasing Hormone (Crh) Signals To Its Receptor Crhr1 During Postnatal Development Of The Mouse Olfactory Bulb, Isabella Garcia, Paramjit K Bhullar, Burak Tepe, Joshua Ortiz-Guzman, Longwen Huang, Alexander M Herman, Lesley Chaboub, Benjamin Deneen, Nicholas J Justice, Benjamin R Arenkiel

Faculty, Staff and Students Publications

Neuropeptides play important physiological functions during distinct behaviors such as arousal, learning, memory, and reproduction. However, the role of local, extrahypothalamic neuropeptide signaling in shaping synapse formation and neuronal plasticity in the brain is not well understood. Here, we characterize the spatiotemporal expression profile of the neuropeptide corticotropin-releasing hormone (CRH) and its receptor CRHR1 in the mouse OB throughout development. We found that CRH-expressing interneurons are present in the external plexiform layer, that its cognate receptor is expressed by granule cells, and show that both CRH and CRHR1 expression enriches in the postnatal period when olfaction becomes important towards olfactory-related …

Preventing Thymus Involution In K5.Cyclin D1 Transgenic Mice Sustains The Naïve T Cell Compartment With Age, Michelle L. Bolner

Dissertations and Theses (Open Access)

The thymus maintains T cell receptor (TCR) repertoire diversity through perpetual release of self-MHC restricted naive T cells. However, thymus involution during the aging process reduces naïve T cell output, leading to defective immune responsiveness to newly encountered antigens. We have found that early thymus involution precipitates the age-associated shift favoring memory T cell dominancy in young control mice. Furthermore, we have shown that age-related thymus involution is prevented in mice expressing a keratin 5 promoter-driven Cyclin D1 (K5.D1) transgene in thymic epithelial cells (TECs). Thymopoiesis occurs normally in K5.D1 transgenic thymi and sustains T cell output to prevent the …

Identifying Protein Kinase Tbk1 As A Novel Inhibitor Of Intestinal Tumorigenesis, Amber L. Mathews

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer diagnosed in women and men， causing almost 600,000 annual deaths worldwide. There is a clear need to understand how CRC forms and progresses in order to improve the strategies of CRC prevention and therapy. A major factor that drives the development of CRC is genetic mutations that lead to activation of oncogenes and inactivation of tumor suppressor genes in intestinal epithelial cells (IECs). In addition, the initiation and progression of CRC involve environmental and immunological factors. In particular, chronic inflammatory conditions are known as an important risk factor for CRC. Intestinal …

Role Of Stat3 In Human Nk Cell Functions, Prasad V. Phatarpekar

Dissertations and Theses (Open Access)

Natural Killer (NK) cells are cytotoxic lymphocytes, which play a critical role in the immune response against malignant cells and microbial infections. NK cells are equipped with activating receptors, which upon detecting ligands expressed on stressed cells induce cytolytic activity of NK cells. Stimulation of NK cell proliferation and priming of NK cytolytic capability are accomplished by cytokines, which mediate their signals mainly through JAK-STAT signaling pathway. Previously, we found that K562 cells genetically modified to express membrane bound IL-21 (mbIL-21), which predominantly activates STAT3, induce robust expansion and activation of human NK cells. Further investigations revealed role of STAT3 …

Mobilization Of Adipose Stromal Cells In Obesity And Cancer By Sparc And Its Proteolytic Isoforms, Chieh Tseng

Dissertations and Theses (Open Access)

Obesity increases cancer risk and progression as shown by epidemiologic studies. However, the underlying pathophysiology remained unclear. Adipose stromal cells (ASC) are adipose tissue-derived mesenchymal progenitors, abundant in white adipose tissue (WAT). In this study, we show that the ASC pool is expanded in obesity and is associated with promoted tumor growth. Next, by using a chimeric GFP-RFP bone marrow transplant model, we observed higher tumor infiltrating cells with ASC phenotype in obese mice compared to lean. Consistently, systemic circulating ASC frequency is six fold higher in tumor-bearing obese mice compared to lean. The tumor infiltrating cells with ASC phenotype …

The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy

Dissertations and Theses (Open Access)

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common malignancy worldwide, with roughly 300,000 cancer related deaths occurring globally each year. The survival of patients with HNSCC has not changed significantly over the past decade, leading investigators to search for promising molecular targets. To identify new treatment targets and biomarkers that could better guide therapy, we previously characterized the genomic alterations from primary HNSCC patient samples. We were among the first to discover that NOTCH1 is one of the most frequently mutated genes in this cancer type. The spectrum of inactivating NOTCH1 mutations in HNSCC suggested …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Molecular Regulation Of Vascular Calcification In Murine Models Of Atherosclerosis, Shanshan Gao

Dissertations and Theses (Open Access)

Background: Calcification occurs often in the atherosclerotic lesions of patients with coronary heart disease and animals with hypercholesterolemia, such as apolipoprotein-E deficient (ApoE-/-) mice. However, the mechanism(s) underlying the development of calcification in atherosclerosis remains unclear. ApoE acts as a lipid transporter, but also has been recognized as a potential regulator of osteogenesis. Little information is available as to whether ApoE has any direct impact on osteogenesis and calcification in vascular smooth muscle cells (VSMC). Several signal transduction pathways play a role in regulation of calcification, including the Wnt/β-catenin system and potentially GTAP, an ubiquitin-conjugating enzyme responsible for protein …

Defining The Molecular Networks Necessary For Thymus Fate And Organogenesis, Kaitlin A. Reeh

Dissertations and Theses (Open Access)

The thymus and parathyroid (PT) glands originate from endodermal progenitors in the bilateral third pharyngeal pouches (3^rd pps). By E11.5 during mouse development, cells committed to the thymus lineage express Foxn1 whereas PT-fated cells express Gcm2. While these transcription factors are required for organ-specific differentiation, the exact molecular mechanisms that specify endodermal progenitors to either the thymus or parathyroid lineage are not well defined. Tbx1 is initially expressed throughout the 3^rd pp endoderm, as it is required for segmentation of the pharyngeal apparatus, but is downregulated in the thymus-fated domain by E10.5. Despite the widely held notion …

Investigating The Role Of Cholesterol Metabolism And Synthesis In Metastasis And Radiation Response In Aggressive Subtypes Of Breast Cancer, Adam Wolfe

Dissertations and Theses (Open Access)

Aggressive breast cancers, triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC), metastasize at a high rate and are notoriously resistant to standard treatments. Research has shown diets high in cholesterol increase the incidence of aggressive breast cancers and pre-clinical research has shown cholesterol can fuel the growth of breast cancer in vivo. Studies at MD Anderson have shown that IBC patients taking cholesterol lowering drugs, statins, have improved survival outcomes, and also statins can improve the response to radiation in vitro. Furthermore, statins have been shown to target the cells with stem like-properties called cancer stem cells (CSCs) which …

Merlin Mediated Regulation Of Hair Follicle Morphogenesis, Megan K. Fentress

Dissertations and Theses (Open Access)

Epidermal homeostasis is paramount for the ongoing function of the skin as the primary barrier between a mammalian organism and the external environment. Homeostasis is achieved through a complex and delicate balance of cell death, cell proliferation and cell differentiation. Critical for regeneration and maintenance of the skin are epidermal stem cells. Within the epidermis two distinct stem cell compartments exist, the bulge and interfollicular/basal stem cell niches, which play a central role in the regeneration of the epidermis through self-renewal and contribution to the differentiated cells of the epidermis. The bulge stem cell niche is established early in epidermal …

Direct Regulation Of Apoptosis By Linear Ubiqutin Chain Assembly Complex (Lubac) And Feedback Regulation Of Lubac Function By Caspases, Donghyun Joo

Dissertations and Theses (Open Access)

Tumor Necrosis Factor-alpha (TNF-α) is a cytokine that plays a role in various cellular processes such as proliferation, differentiation (mainly through NF-κB signaling) and death (via apoptosis signaling). Recently, linear ubiquitination by LUBAC (linear ubiquitin chain assembly complex) was reported to have a regulatory function in TNF-α mediated NF-κB activation. Although LUBAC is suggested to control not only NF-kB signaling but also the apoptosis pathway, the precise mechanism of apoptosis regulation remains unknown. Moreover, NF-κB and apoptosis pathways have opposed but fundamental functions for various cellular processes. Although these two pathways actively interplay to balance the death and survival, the …

Histone H3 K4 Methylation Regulates The Spindle Assembly Checkpoint Through Direct Binding Of Multiple Checkpoint Components And Cdc20, Andria C. Schibler

Dissertations and Theses (Open Access)

Histone H3K4 methylation is conserved across species and is associated with active transcription. By using Saccharomyces cerevisiae, we found histone H3K4 methylation has a previously unknown role in regulating mitosis through the Spindle Assembly Checkpoint. The Spindle Assembly Checkpoint ensures duplicated chromosomes are segregated correctly and each daughter cell receives one full copy of the genome. Our data show SET1 mutants and histone H3K4 mutants display a resistance to the mitotic poison, benomyl. Moreover methylated histone H3 directly binds to Spindle Assembly Checkpoint proteins Bub3 and Mad2 as well as the activator of the Anaphase Promoting Complex (APC) protein …

Induction Of Caspase-Dependent Death By Proteasome Targeted Therapy In Glioblastoma, Christa A. Manton

Dissertations and Theses (Open Access)

New therapeutic options are needed for glioblastoma, a deadly disease with a median survival of only 14 months with current treatment. The proteasome inhibitor bortezomib (BTZ) shows efficacy in cancers like myeloma, but its clinical utility in other cancer types has been more limited. Newer proteasome inhibitors such as marizomib (MRZ) have unique inhibitory and death inducing properties that have not been well examined in GBM. Additionally, targeting other components of the ubiquitin-proteasome system is possible, but has not been explored in GBM. Questions also still remain about the ability of BTZ and MRZ to be delivered to brain tumors …

Igfbp2 Potentiates Egfr-Stat3 Signaling In Glioma, Yingxuan Chua

Dissertations and Theses (Open Access)

Gliomas are clinically challenging brain tumors with dismal survival rates due to its infiltrative nature and ineffective standard therapy. Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the contributions of intracellular IGFBP2 to tumor development and progression are poorly understood. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via …

Src Homology 2 Domain-Containing 5’-Inositol Phosphatase-2 (Ship2) Is An Effector Of Lymphatic Dysfunction, Germaine D. Agollah

Dissertations and Theses (Open Access)

The lymphatic system is essential for the transport of excess fluid, protein, and foreign materials from interstitial tissues to lymph nodes; for immune surveillance, and to maintain fluid homeostasis. Dysregulated lymphatics can be attributed to pathological conditions including tumor metastasis, inflammation, chronic wounds, obesity, blood vascular disorders, and lymphedema. Of these, lymphedema is the most extreme of lymphatic disorders and is represented by a spectrum of symptoms ranging from mild, subtle presentation to severe, disfiguring, overt presentation. Lymphedema is more manageable in the early stages of disease but severely reduces quality of life with progression. Due to lack of molecular …

Elucidating The Role Of Rumi And O-Glucosylation In The Drosophila Eye, Amanda Haltom

Dissertations and Theses (Open Access)

Rumi is a protein O-glucosyltransferase that adds the sugar O-glucose onto the serine in the target sequence C-S-X-S-(P/A)-C found within properly folded EGF repeats. It was first discovered to modify the Drosophila Notch extracellular domain and to be required for Notch signaling in a temperature dependent manner, but other targets of Rumi remained unknown. Several other proteins in the Drosophila proteome harbor multiple consensus sequence highly predictive of O-glucose, including the transmembrane protein Crumbs and the secreted protein Eyes shut (Eys). Both of these proteins are required for proper eye development and mutations in their human homologs …

Dna Polymerase Θ (Polq) And The Cellular Defense Against Dna Damage, Matthew J. Yousefzadeh

Dissertations and Theses (Open Access)

In mammalian cells, DNA polymerase θ (POLQ) is an unusual specialized DNA polymerase whose in vivo function is under active investigation. The protein is comprised of an N-terminal helicase-like domain, a C-terminal DNA polymerase domain, and a large central domain that spans between the two. This arrangement is also found in the Drosophila Mus308 protein, which helps confer resistance to DNA interstrand crosslinking agents. Homologs of POLQ and Mus308 are found in eukaryotes, including plants, but a comparison of phenotypes suggests that not all of these genes are functional orthologs. Flies with defective Mus308 are sensitive to DNA interstrand crosslinking …

Cancer Associated Fibroblast Derived Angiogenic Factor Mfap5 In Ovarian Cancer Progression, Sze Lee Cecilia Leung

Dissertations and Theses (Open Access)

Advanced stage ovarian cancer is the most lethal gynecologic malignancy. No major improvement on patient survival has been achieved in the past decade. Therefore, identification of predictive or prognostic markers and further understanding of the molecular mechanisms in ovarian cancer progression are of paramount importance.

While cancer cells have always been the targets for the identification of prognostic and predictive markers, the potential for developing new diagnosis and treatments based on the tumor supporting stromal microenvironment is relatively unexplored. Using transcriptome profiling analysis on microdissected stromal and epithelial components of normal and malignant ovarian tissues, we identified a gene signature …

Microrna-200 Regulates Ecm-Dependent Β1-Integrin/Fak Signaling And Cancer Cell Invasion, Christin Ungewiss

Dissertations and Theses (Open Access)

The microRNA-200 family is known to be a master regulator of the epithelial-to-mesenchymal transition, partially through its double-negative feedback loop with the transcriptional repressor Zeb1, yet the mechanisms on how miR-200 controls the invasive phenotype are not fully understood. Recent studies have shown that the miR-200/Zeb1 axis regulates cell-cell and cell-matrix interactions, but it has also been demonstrated that cell-intrinsic changes are insufficient to drive cancer cell invasion, leading us to focus on specific cell-matrix interactions required to activate tumor cell invasion and metastases. We have shown through 3D studies that the Integrin β1-collagen I contact is critical in mediating …

Atp-Citrate Lyase Links Cyclin E To Cellular Metabolism In Breast Cancer, Kim Lucenay

Dissertations and Theses (Open Access)

Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are …

Understanding The Role Of Sumoylation In Regulating Lkb1 Function, Joan W. Ritho

Dissertations and Theses (Open Access)

Energy homeostasis in a cell is critical for its survival during metabolic stress. Liver kinase B1 (LKB1), one of the key regulators of cellular energy balance, was initially discovered as a tumor suppressor mutated in patients with Peutz-Jeghers syndrome. Germline mutations in LKB1 predispose patients to develop several benign and malignant tumors including gastrointestinal and lung cancers. In 2003, several groups demonstrated that LKB1is a major upstream kinase of the energy sensor AMP-activated protein kinase (AMPK), directly associating it with the regulation of energy balance in cells. During energy stress, LKB1 phosphorylates AMPK at threonine 172 (T172) resulting in AMPK …

The Role Of Autophagy In The Sensitivity Of Osteosarcoma Cells To Gemcitabine Treatment, Janice M. Santiago-O'Farrill

Dissertations and Theses (Open Access)

Despite treatment improvement for osteosarcoma (OS), overall survival has remained unchanged in the last 20 years. Pulmonary metastasis continues to be the main cause of death; novel therapeutic strategies are urgently needed to improve the survival rate of these patients. Previous data in our laboratory has demonstrated that aerosol gemcitabine (GCB) treatment has a significant therapeutic effect on metastatic OS. However, treatment efficacy is decreased due to acquired resistance by a population of tumor cells that fails to respond to treatment. Recent studies have implicated autophagy as a resistance mechanism in various types of cancer. The purpose of this study …

Actions Of Pi3k-Delta Inhibitor, Idelalisib, And Its Combination With Bendamustine In Chronic Lymphocytic Leukemia, Prexy Modi

Dissertations and Theses (Open Access)

Class I phosphatidylinositol 3-kinase isoforms (α, β, δ, and γ) play a major role in cancer cell growth and survival. PI3K α and β are most studied. PI3K pathway is highly dysregulated in many cancers and aberrant PI3K signaling is associated with oncogene mutations and disease progression in solid tumors and in hematologic malignancies.

Chronic lymphocytic leukemia (CLL) is driven by B-cell receptor (BCR) signaling that promotes B-cell proliferation and survival. PI3K is a critical node in BCR pathway and PI3Kδ has a pivotal role in B-cell development and maintenance and this isoform is over-expressed in many B-cell malignancies, including …