Digital Commons Network^™

Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity …

Cxcl10 Chemokine Regulates Heterogeneity Of The Cd8+ T Cell Response And Viral Set Point During Chronic Infection, Aleksandra J Ozga, Melvyn T Chow, Mateus E Lopes, Rachel L Servis, Mauro Di Pilato, Philippe Dehio, Jeffrey Lian, Thorsten R Mempel, Andrew D Luster

Faculty, Staff and Student Publications

CD8+ T cells responding to chronic infection adapt an altered differentiation program that provides some restrain on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8+ T cell differentiation in chronic infection has important therapeutic implications. Here, we found that the chemokine receptor CXCR3 was highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulated the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 was produced by inflammatory monocytes …

P300 Or Cbp Is Required For Insulin-Stimulated Glucose Uptake In Skeletal Muscle And Adipocytes, Vitor F. Martins, Gretchen A. Meyer, Et Al.

2020-Current year OA Pubs

While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this …

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

Emergence Of Clinical Clostridioides Difficile Isolates With Decreased Susceptibility To Vancomycin, Charles Darkoh, Kadiatou Keita, Chioma Odo, Micah Oyaro, Eric L Brown, Cesar A Arias, Blake M Hanson, Herbert L Dupont

Faculty, Staff and Student Publications

BACKGROUND: Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few antibiotics recommended for both nonsevere and severe CDI cases. We sought to determine whether vancomycin nonsusceptible C. difficile strains are circulating in the patient population.

METHODS: Stool samples from patients with CDI were collected from 438 and 98 patients at a large university hospital in Houston, Texas, and Nairobi, Kenya, respectively. The stools were examined for the presence of vancomycin and metronidazole nonsusceptible C. difficile using broth dilution culture, Etest (BioMérieux, France), polymerase chain reaction (PCR), whole-genome sequencing, …

Constitutively Active Sarm1 Variants That Induce Neuropathy Are Enriched In Als Patients, A Joseph Bloom, Xianrong Mao, Amy Strickland, Yo Sasaki, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

BACKGROUND: In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD

METHODS: To investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo.

RESULTS: Twelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive …

Aav5 Delivery Of Crispr-Cas9 Supports Effective Genome Editing In Mouse Lung Airway, Shun-Qing Liang, Christopher J Walkey, Alexa E Martinez, Qin Su, Mary E Dickinson, Dan Wang, William R Lagor, Jason D Heaney, Guangping Gao, Wen Xue

Faculty, Staff and Students Publications

Genome editing in the lung has the potential to provide long-term expression of therapeutic protein to treat lung genetic diseases. Yet efficient delivery of CRISPR to the lung remains a challenge. The NIH Somatic Cell Genome Editing (SCGE) Consortium is developing safe and effective methods for genome editing in disease tissues. Methods developed by consortium members are independently validated by the SCGE small animal testing center to establish rigor and reproducibility. We have developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing of a lox-stop-lox-Tomato reporter in mouse lung airway. After intratracheal injection of the …

Inflammatory Response To Sleep Fragmentation In Skeletal, Cardiac, And Smooth Muscle Tissues In Female Mice, Patton Allen

Mahurin Honors College Capstone Experience/Thesis Projects

Sleep is a critical process that the body undergoes. When sleep is interrupted, so that an individual is awakened for some period before going back into sleep, the sleep can be described as fragmented. Studies in the past have shown that sleep fragmentation (SF) promotes an inflammatory environment, especially in the brain and peripheral tissue. However, studies have not been conducted to observe inflammatory responses in muscle. To examine this, C57BL/6J female mice were subjected to either a control group (no SF) or a SF group which involved using an automated SF chamber to disrupt sleep every 2 min over …

Ifn-Γ Transforms The Transcriptomic Landscape And Triggers Myeloid Cell Hyperresponsiveness To Cause Lethal Lung Injury, Atul K. Verma, Michael Mckelvey, Md Bashir Uddin, Sunil Palani, Meng Niu, Christopher Bauer, Shengjun Shao, Keer Sun

Journal Articles: Pathology and Microbiology

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes …

An Artifact In Intracellular Cytokine Staining For Studying T Cell Responses And Its Alleviation., Zheng Gong, Qing Li, Jiayuan Shi, Guangwen Ren

Faculty Research 2022

Intracellular cytokine staining (ICS) is a widely employed ex vivo method for quantitative determination of the activation status of immune cells, most often applied to T cells. ICS test samples are commonly prepared from animal or human tissues as unpurified cell mixtures, and cell-specific cytokine signals are subsequently discriminated by gating strategies using flow cytometry. Here, we show that when ICS samples contain Ly6G⁺ neutrophils, neutrophils are ex vivo activated by an ICS reagent - phorbol myristate acetate (PMA) - which leads to hydrogen peroxide (H₂O₂) release and death of cytokine-expressing T cells. This artifact …

The Th1/Tfh-Like Biased Responses Elicited By The Rasp-1 Innate Adjuvant Are Dependent On Trif And Type I Ifn Receptor Pathways., Parakkal Jovvian George, Radu Marches, Djamel Nehar-Belaid, Jacques Banchereau, Sara Lustigman

Faculty Research 2022

No abstract provided.

Witch Nails (Krt90whnl): A Spontaneous Mouse Mutation Affecting Nail Growth And Development., John P Sundberg, Hannah Galantino-Homer, Heather Fairfield, Patricia F. Ward-Bailey, Belinda S. Harris, Melissa L. Berry, C Herbert Pratt, Nicholas E Gott, Lesley S Bechtold, Pauline R Kaplan, Blythe P Durbin-Johnson, David M Rocke, Robert H Rice

Faculty Research 2022

Numerous single gene mutations identified in humans and mice result in nail deformities with many similarities between the species. A spontaneous, autosomal, recessive mutation called witch nails (whnl) is described here where the distal nail matrix and nail bed undergo degenerative changes resulting in formation of an abnormal nail plate causing mice to develop long, curved nails. This mutation arose spontaneously in a colony of MRL/MpJ-Faslpr/J at The Jackson Laboratory. Homozygous mutant mice are recognizable by 8 weeks of age by their long, curved nails. The whnl mutation, mapped on Chromosome 15, is due to a 7-bp insertion identified in …

Mintruls: Prediction Of Mirna-Mrna Target Site Interactions Using Regularized Least Square Method, Sushil Kumar Shakyawar, Siddesh Southekal, Chittibabu Guda

Journal Articles: Genetics, Cell Biology & Anatomy

Identification of miRNA-mRNA interactions is critical to understand the new paradigms in gene regulation. Existing methods show suboptimal performance owing to inappropriate feature selection and limited integration of intuitive biological features of both miRNAs and mRNAs. The present regularized least square-based method, mintRULS, employs features of miRNAs and their target sites using pairwise similarity metrics based on free energy, sequence and repeat identities, and target site accessibility to predict miRNA-target site interactions. We hypothesized that miRNAs sharing similar structural and functional features are more likely to target the same mRNA, and conversely, mRNAs with similar features can be targeted by …

Identification Of Gut Bacteria Such As Lactobacillus Johnsonii That Disseminate To Systemic Tissues Of Wild Type And Myd88-/- Mice, Sreeram Udayan, Panagiota Stamou, Fiona Crispie, Ana Hickey, Alexandria N Floyd, Chyi-Song Hsieh, Paul D Cotter, Orla O'Sullivan, Silvia Melgar, Paul W O'Toole, Rodney D Newberry, Valerio Rossini, Ken Nally

Open Access Publications

In healthy hosts the gut microbiota is restricted to gut tissues by several barriers some of which require MyD88-dependent innate immune sensor pathways. Nevertheless, some gut taxa have been reported to disseminate to systemic tissues. However, the extent to which this normally occurs during homeostasis in healthy organisms is still unknown. In this study, we recovered viable gut bacteria from systemic tissues of healthy wild type (WT) and MyD88

Crispr-Krispr: A Method To Identify On-Target And Random Insertion Of Donor Dnas And Their Characterization In Knock-In Mice, Masayuki Tanaka, Keiko Yokoyama, Hideki Hayashi, Sanae Isaki, Kanae Kitatani, Ting Wang, Hisako Kawata, Hideyuki Matsuzawa, Channabasavaiah B. Gurumurthy, Hiromi Miura, Masato Ohtsuka

Journal Articles: Pharmacology & Experimental Neuroscience

CRISPR tools can generate knockout and knock-in animal models easily, but the models can contain off-target genomic lesions or random insertions of donor DNAs. Simpler methods to identify off-target lesions and random insertions, using tail or earpiece DNA, are unavailable. We develop CRISPR-KRISPR (CRISPR-Knock-ins and Random Inserts Searching PRotocol), a method to identify both off-target lesions and random insertions. CRISPR-KRISPR uses as little as 3.4 μg of genomic DNA; thus, it can be easily incorporated as an additional step to genotype founder animals for further breeding.

Ecdysoneless Overexpression Drives Mammary Tumorigenesis Through Upregulation Of C-Myc And Glucose Metabolism, Bhopal C. Mohapatra, Sameer Mirza, Aditya Bele, Channabasavaiah B. Gurumurthy, Mohsin Raza, Irfana Saleem, Matthew D. Storck, Aniruddha Sarkar, Sai Sundeep Kollala, Surendra K. Shukla, Siddesh Southekal, Kay-Uwe Wagner, Fang Qiu, Subodh M. Lele, Mansour A. Alsaleem, Emad A. Rakha, Chittibabu Guda, Pankaj K. Singh, Robert D. Cardiff, Hamid Band, Vimla Band

Journal Articles: Pharmacology & Experimental Neuroscience

Ecdysoneless (ECD) protein is essential for embryogenesis, cell-cycle progression, and cellular stress mitigation with an emerging role in mRNA biogenesis. We have previously shown that ECD protein as well as its mRNA are overexpressed in breast cancer and ECD overexpression predicts shorter survival in patients with breast cancer. However, the genetic evidence for an oncogenic role of ECD has not been established. Here, we generated transgenic mice with mammary epithelium-targeted overexpression of an inducible human ECD transgene (ECDTg). Significantly, ECDTg mice develop mammary hyperplasia, preneoplastic lesions, and heterogeneous tumors with occasional lung metastasis. ECDTg tumors exhibit epithelial to mesenchymal transition …

Differential Methylation Patterns In Lean And Obese Non-Alcoholic Steatohepatitis-Associated Hepatocellular Carcinoma, Emma Hymel, Kurt W. Fisher, Evi A. Farazi

Journal Articles: Epidemiology

BACKGROUND: Nonalcoholic fatty liver disease affects about 24% of the world's population and may progress to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). While more common in those that are obese, NASH-HCC can develop in lean individuals. The mechanisms by which HCC develops and the role of epigenetic changes in the context of obesity and normal weight are not well understood.

METHODS: In this study, we used previously generated mouse models of lean and obese HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to evaluate methylation differences in HCC progression in lean versus …

Epidermal Growth Factor Receptor Inhibition Is Protective In Hyperoxia-Induced Lung Injury., Zachary M Harris, Ying Sun, John Joerns, Brian Clark, Buqu Hu, Asawari Korde, Lokesh Sharma, Hyeon Jun Shin, Edward P Manning, Lindsey Placek, Derya Unutmaz, Gail Stanley, Hyung Chun, Maor Sauler, Govindarajan Rajagopalan, Xuchen Zhang, Min-Jong Kang, Jonathan L Koff

Faculty Research 2022

AIMS: Studies have linked severe hyperoxia, or prolonged exposure to very high oxygen levels, with worse clinical outcomes. This study investigated the role of epidermal growth factor receptor (EGFR) in hyperoxia-induced lung injury at very high oxygen levels (>95%).

RESULTS: Effects of severe hyperoxia (100% oxygen) were studied in mice with genetically inhibited EGFR and wild-type littermates. Despite the established role of EGFR in lung repair, EGFR inhibition led to improved survival and reduced acute lung injury, which prompted an investigation into this protective mechanism. Endothelial EGFR genetic knockout did not confer protection. EGFR inhibition led to decreased levels …

Giardial Lipid Rafts Share Virulence Factors With Secreted Vesicles And Participate In Parasitic Infection In Mice, Brian I. Grajeda, Atasi De Chatterjee, Carmen M. Villalobos, Breanna C. Pence, Cameron C. Ellis, Vanessa Enriquez, Sourav Roy, Sukla Roychowdhury, Aaron K. Neumann, Igor C. Almeida, Steven E. Patterson, Siddhartha Das

Pathology Research and Scholarship

Giardia lamblia, a protozoan parasite, is a major cause of waterborne infection, worldwide. While the trophozoite form of this parasite induces pathological symptoms in the gut, the cyst form transmits the infection. Since Giardia is a noninvasive parasite, the actual mechanism by which it causes disease remains elusive. We have previously reported that Giardia assembles cholesterol and GM1 glycosphingolipid-enriched lipid rafts (LRs) that participate in encystation and cyst production. To further delineate the role of LRs in pathogenesis, we isolated LRs from Giardia and subjected them to proteomic analysis. Various cellular proteins including potential virulence factors-e.g., giardins, variant surface …

Dietary Isoflavones Alter Gut Microbiota And Lipopolysaccharide Biosynthesis To Reduce Inflammation, Sudeep Ghimire, Nicole M. Cady, Peter Lehman, Stephanie R. Peterson, Shailesh K. Shahi, Faraz Rashid, Shailendra Giri, Ashutosh K. Mangalam

Neurology Articles

The etiopathogenesis of multiple sclerosis (MS) is strongly affected by environmental factors such as diet and the gut microbiota. An isoflavone-rich (ISO) diet was previously shown to reduce the severity of MS in the animal model experimental autoimmune encephalomyelitis (EAE). Translation of this concept to clinical trial where dietary isoflavones may be recommended for MS patients will require preliminary evidence that providing the isoflavone-rich diet to people with MS (PwMS) who lack phytoestrogen-metabolizing bacteria has beneficial effects. We have previously shown that the gut microbiota of PwMS resembles the gut microbiota of mice raised under a phytoestrogen-free (phyto-free) diet in …

The Role Of Action Potential Changes In Depolarization-Induced Failure Of Excitation Contraction Coupling In Mouse Skeletal Muscle, Xueyong Wang, Murad Nawaz, Chris Dupont, Jessica H. Myers, Steve R.A. Burke, Roger A. Bannister, Brent D. Foy, Andrew A. Voss, Mark M. Rich

Physics Faculty Publications

Excitation-contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, intensive care unit acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K+ is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a narrow range of resting potentials. Simultaneous imaging of Ca2+ transients and recording of action potentials (APs) demonstrated failure to generate Ca2+ transients when APs peaked at potentials more negative than –30mV. An AP property that closely …

Assessing Sex-Specific Circadian, Metabolic, And Cognitive Phenotypes In The Aβpp/Ps1 And Appnl-F/Nl-F Models Of Alzheimer's Disease., Jesse Britz, Emmanuel Ojo, Asmita Dhukhwa, Takashi Saito, Takaomi C Saido, Erin R Hascup, Kevin N Hascup, Shelley A Tischkau

Articles

BACKGROUND: Circadian disruption has long been recognized as a symptom of Alzheimer's disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits.

OBJECTIVE: This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months.

METHODS: Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes.

RESULTS: Sex-dependent hyperactivity in AβPP/PS1 mice was …

Assessing Sex-Specific Circadian, Metabolic, And Cognitive Phenotypes In The Aβpp/Ps1 And Appnl-F/Nl-F Models Of Alzheimer's Disease., Jesse Britz, Emmanuel Ojo, Asmita Dhukhwa, Takashi Saito, Takaomi C Saido, Erin R Hascup, Kevin N Hascup, Shelley A Tischkau

Articles

BACKGROUND: Circadian disruption has long been recognized as a symptom of Alzheimer's disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits.

OBJECTIVE: This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months.

METHODS: Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes.

RESULTS: Sex-dependent hyperactivity in AβPP/PS1 mice was …

Amigo1 Promotes Axon Growth And Territory Matching In The Retina, Florentina Soto, Ning Shen, Daniel Kerschensteiner

Open Access Publications

Dendrite and axon arbor sizes are critical to neuronal function and vary widely between different neuron types. The relative dendrite and axon sizes of synaptic partners control signal convergence and divergence in neural circuits. The developmental mechanisms that determine cell-type-specific dendrite and axon size and match synaptic partners' arbor territories remain obscure. Here, we discover that retinal horizontal cells express the leucine-rich repeat domain cell adhesion molecule AMIGO1. Horizontal cells provide pathway-specific feedback to photoreceptors-horizontal cell axons to rods and horizontal cell dendrites to cones. AMIGO1 selectively expands the size of horizontal cell axons. When

Mechanisms Underlying Pre- And Postnatal Development Of The Mouse Vomeronasal Organ, Raghu Ram Katreddi

Legacy Theses & Dissertations (2009 - 2024)

The Vomeronasal organ (VNO) is a specialized olfactory sensory organ located in the ventral region of the nasal cavity in rodents. The vomeronasal epithelium (VNE) of rodents is composed of 2 major types of vomeronasal sensory neurons (VSNs): 1) VSNs distributed in the apical VNE regions that express vomeronasal type-1 receptors (V1Rs) and the G protein subunit Gi2, and 2) VSNs in the basal territories of the VNE that express vomeronasal type-2 receptors (V2Rs) and the G subunit Go. Besides these two neuronal types, VNE also accommodate a third non-neuronal cell type called Sustentacular cells that lie anatomically above apical …

Elucidating The Effects Of Erα: Isoform Expression And Differential Receptor Localization In Immune Function, Cameron Leyers

MUSC Theses and Dissertations

Estrogen can be anti- or pro-inflammatory depending on milieu and has a role in increased incidence of lupus in reproductive age women versus men. Estrogen’s pleiotropic effects are in part due to Estrogen receptorα (ERα) and its variants that localize to cytoplasmic pools, nuclear regions and to the membrane. To understand the role of sex hormone receptors in immune responses, we investigated the effects of altered ERα isoform overexpression in dendritic and B cells. Toll like receptor 7 (TLR7) stimulated endpoints, often dysregulated in lupus were also investigated. Genetically modified MOER (membrane-only ERα) and NOER (nuclear-only ERα) mice were used …

Ret Signaling Pathway And Ret Inhibitors In Human Cancer, Angelina T Regua, Mariana Najjar, Hui-Wen Lo

Faculty, Staff and Student Publications

Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or …

The Impact Of Protein Tyrosine Phosphatase 1b On Impaired Insulin Signaling And Cognitive Impairment, Alexus S. Williams

MUSC Theses and Dissertations

High-fat diet (HFD) in mice, a mouse model of diet-induced obesity, display cognitive deficits, which correlate with hyperinsulinemia and reduced levels of brain insulin. The binding of insulin to the insulin receptor leads to tyrosine auto-phosphorylation of the receptor, which is a necessary step for the initiation of insulin transport. Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues on the Insulin receptor. We hypothesize that diet-induced increases in PTP1B levels inhibits insulin receptor signaling contributing to cognitive impairment. To accomplish this, PTP1B levels, tyrosine phosphorylation, and cognition was assessed in mice placed on either a standard diet (STD) or HFD …

Gut Microbiome Dysbiosis In Antibiotic-Treated Covid-19 Patients Is Associated With Microbial Translocation And Bacteremia, Lucie Bernard-Raichon, Mericien Venzon, Jon Klein, Jordan E. Axelrad, Chenzhen Zhang, Alexis P. Sullivan, Grant A. Hussey, Arnau Casanovas-Massana, Maria G. Noval, Ana M. Valero-Jimenez, Juan Gago, Gregory Putzel, Alejandro Pironti, Evan Wilder, Yale Impact Research Team, Lorna E. Thorpe, Dan R. Littman, Meike Dittmann, Kenneth A. Stapleford, Bo Shopsin, Victor J. Torres, Albert I. Ko, Akiko Iwasaki, Ken Cadwell, Jonas Schluter, Abeer Obaid, Alice Lu-Culligan, Allison Nelson, Anderson Brito, Angela Nunez, Anjelica Martin, Annie Watkins, Bertie Geng, Chaney Kalinich, Christina Harden, Codruta Todeasa, Cole Jensen, Daniel Kim, David Mcdonald, Denise Shepard, Edward Courchaine, Elizabeth B. White, Eric Song, Erin Silva, Eriko Kudo, Giuseppe Deluliis, Harold Rahming, Hong-Jai Park, Irene Matos, Jessica Nouws, Jordan Valdez, Joseph R. Fauver, Joseph Lim, Kadi-Ann Rose, Kelly Anastasio, Kristina Brower, Laura Glick, Lokesh Sharma, Lorenzo Sewanan, Lynda Knaggs, Maksym Minasyan, Maria Batsu, Mary Petrone, Maxine Kuang, Maura Nakahata, Melissa Campbell, Melissa Linehan, Michael H. Askenase, Michael Simonov, Mikhail Smolgovsky, Nicole Sonnert, Nida Naushad

Journal Articles: Epidemiology

Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. …