Digital Commons Network^™

Smarcb1 Regulates The Hypoxic Stress Response In Sickle Cell Trait, Melinda Soeung, Luigi Perelli, Ziheng Chen, Eleonora Dondossola, I-Lin Ho, Federica Carbone, Li Zhang, Hania Khan, Courtney N Le, Cihui Zhu, Michael D Peoples, Ningping Feng, Shan Jiang, Niki Millward Zacharias, Rosalba Minelli, Daniel D Shapiro, Angela K Deem, Sisi Gao, Emily H Cheng, Donatella Lucchetti, Cheryl L Walker, Alessandro Carugo, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Nizar M Tannir, Giulio F Draetta, Pavlos Msaouel, Giannicola Genovese

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels …

Beclin-1-Dependent Autophagy, But Not Apoptosis, Is Critical For Stem-Cell-Mediated Endometrial Programming And The Establishment Of Pregnancy, Pooja Popli, Suni Tang, Sangappa B Chadchan, Chandni Talwar, Edmund B Rucker, Xiaoming Guan, Diana Monsivais, John P Lydon, Christina L Stallings, Kelle H Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin …

The First Transcriptomic Atlas Of The Adult Lacrimal Gland Reveals Epithelial Complexity And Identifies Novel Progenitor Cells In Mice, Vanessa Delcroix, Olivier Mauduit, Hyun Soo Lee, Anastasiia Ivanova, Takeshi Umazume, Sarah M Knox, Cintia S De Paiva, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

The lacrimal gland (LG) secretes aqueous tears. Previous studies have provided insights into the cell lineage relationships during tissue morphogenesis. However, little is known about the cell types composing the adult LG and their progenitors. Using scRNAseq, we established the first comprehensive cell atlas of the adult mouse LG to investigate the cell hierarchy, its secretory repertoire, and the sex differences. Our analysis uncovered the complexity of the stromal landscape. Epithelium subclustering revealed myoepithelial cells, acinar subsets, and two novel acinar subpopulations: Tfrc^hi and Car6^hi cells. The ductal compartment contained Wfdc2+ multilayered ducts and an Ltf+ cluster formed …

Voluntary Wheel Running Promotes Resilience To The Behavioral Effects Of Unpredictable Chronic Mild Stress In Male And Female Mice., Elias Elias, Ariel Y Zhang, Abigail G White, Matthew J Pyle, Melissa T Manners

College of Science & Mathematics Departmental Research

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. …

Using Mass Spectrometry Imaging To Map Fluxes Quantitatively In The Tumor Ecosystem, Michaela Schwaiger-Haber, Ethan Stancliffe, Dhanalakshmi S Anbukumar, Blake Sells, Jia Yi, Kevin Cho, Kayla Adkins-Travis, Milan G Chheda, Leah P Shriver, Gary J Patti

2020-Current year OA Pubs

Tumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix …

Deepmicetl: A Deep Transfer Learning Based Prediction Of Mice Cardiac Conduction Diseases Using Early Electrocardiograms, Ying Liao, Yisha Xiang, Mingjie Zheng, Jun Wang

Faculty, Staff and Student Publications

Cardiac conduction disease is a major cause of morbidity and mortality worldwide. There is considerable clinical significance and an emerging need of early detection of these diseases for preventive treatment success before more severe arrhythmias occur. However, developing such early screening tools is challenging due to the lack of early electrocardiograms (ECGs) before symptoms occur in patients. Mouse models are widely used in cardiac arrhythmia research. The goal of this paper is to develop deep learning models to predict cardiac conduction diseases in mice using their early ECGs. We hypothesize that mutant mice present subtle abnormalities in their early ECGs …

Cxcl8/Cxcr2 Signaling Mediates Bone Marrow Fibrosis And Is A Therapeutic Target In Myelofibrosis, Andrew J Dunbar, Dongjoo Kim, Min Lu, Mirko Farina, Robert L Bowman, Julie L Yang, Young Park, Abdul Karzai, Wenbin Xiao, Zach Zaroogian, Kavi O'Connor, Shoron Mowla, Francesca Gobbo, Paola Verachi, Fabrizio Martelli, Giuseppe Sarli, Lijuan Xia, Nada Elmansy, Maria Kleppe, Zhuo Chen, Yang Xiao, Erin Mcgovern, Jenna Snyder, Aishwarya Krishnan, Corrine Hill, Keith Cordner, Anouar Zouak, Mohamed E Salama, Jayden Yohai, Eric Tucker, Jonathan Chen, Jing Zhou, Timothy Mcconnell, Anna R Migliaccio, Richard Koche, Raajit Rampal, Rong Fan, Ross L Levine, Ronald Hoffman

Faculty, Staff and Student Publications

Proinflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution are yet to be fully elucidated. Previously, we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB proinflammatory signaling in MF development. Using single-cell transcriptional and cytokine-secretion studies of primary cells from patients with MF and the human MPLW515L (hMPLW515L) murine model of MF, we extend our previous work and delineate the role of …

Modulating Fast Skeletal Muscle Contraction Protects Skeletal Muscle In Animal Models Of Duchenne Muscular Dystrophy, Alan J. Russell, Twlya I. Juehne, Jinsheng Yu, Et Al.

2020-Current year OA Pubs

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast …

Efficient Cancer Modeling Through Crispr-Cas9/Hdr-Based Somatic Precision Gene Editing In Mice, Wen Bu, Chad J Creighton, Kelsey S Heavener, Carolina Gutierrez, Yongchao Dou, Amy T Ku, Yiqun Zhang, Weiyu Jiang, Jazmin Urrutia, Wen Jiang, Fei Yue, Luyu Jia, Ahmed Atef Ibrahim, Bing Zhang, Shixia Huang, Yi Li

Faculty, Staff and Student Publications

CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either

Co-Clinical Imaging Metadata Information (Cimi) For Cancer Research To Promote Open Science, Standardization, And Reproducibility In Preclinical Imaging, Stephen M Moore, James D Quirk, Andrew W Lassiter, Richard Laforest, Gregory D Ayers, Cristian T Badea, Andriy Y Fedorov, Paul E Kinahan, Matthew Holbrook, Peder E Z Larson, Renuka Sriram, Thomas L Chenevert, Dariya Malyarenko, John Kurhanewicz, A Mcgarry Houghton, Brian D Ross, Stephen Pickup, James C Gee, Rong Zhou, Seth T Gammon, Henry Charles Manning, Raheleh Roudi, Heike E Daldrup-Link, Michael T Lewis, Daniel L Rubin, Thomas E Yankeelov, Kooresh I Shoghi

Faculty, Staff and Students Publications

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an …

Co-Clinical Imaging Metadata Information (Cimi) For Cancer Research To Promote Open Science, Standardization, And Reproducibility In Preclinical Imaging, Stephen M Moore, James D Quirk, Andrew W Lassiter, Richard Laforest, Kooresh I Shoghi, Et Al.

2020-Current year OA Pubs

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an …

Mechanisms Underlying The Antiarrhythmic Effect Of Arumenamide-787 In Experimental Models Of The J Wave Syndromes And Hypothermia, José M. Di Diego, Hector Barajas-Martinez, Robert Cox, Victoria M Robinson, Joseph Jung, Mohamed Fouda, Mena Abdelsayed, Peter C Ruben, Charles Antzelevitch

Department of Medicine Faculty Papers

BACKGROUND: Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia.

METHODS: We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG …

Rapid Neuroplasticity Changes And Response To Intravenous Ketamine: A Randomized Controlled Trial In Treatment-Resistant Depression, Jared Kopelman, Timothy A Keller, Benjamin Panny, Angela Griffo, Michelle Degutis, Crystal Spotts, Nicolas Cruz, Elizabeth Bell, Kevin Do-Nguyen, Meredith L Wallace, Sanjay J Mathew, Robert H Howland, Rebecca B Price

Staff and Researcher Publications

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of …

Tfeb And Tfe3 Drive Kidney Cystogenesis And Tumorigenesis, Chiara Di Malta, Angela Zampelli, Letizia Granieri, Claudia Vilardo, Rossella De Cegli, Laura Cinque, Edoardo Nusco, Salvatore Pece, Daniela Tosoni, Francesca Sanguedolce, Nicolina Cristina Sorrentino, Maria J Merino, Deborah Nielsen, Ramaprasad Srinivasan, Mark W Ball, Christopher J Ricketts, Cathy D Vocke, Martin Lang, Baktiar Karim, Luisa Lanfrancone, Laura S Schmidt, W Marston Linehan, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb …

The Dark Kinase Stk32a Regulates Hair Cell Planar Polarity Opposite Of Emx2 In The Developing Mouse Inner Ear., Shihai Jia, Evan M Ratzan, Ellison J Goodrich, Raisa Abrar, Luke Heiland, Basile Tarchini, Michael R Deans

Faculty Research 2023

The vestibular maculae of the inner ear contain sensory receptor hair cells that detect linear acceleration and contribute to equilibrioception to coordinate posture and ambulatory movements. These hair cells are divided between two groups, separated by a line of polarity reversal (LPR), with oppositely oriented planar-polarized stereociliary bundles that detect motion in opposite directions. The transcription factor EMX2 is known to establish this planar polarized organization in mouse by regulating the distribution of the transmembrane receptor GPR156 at hair cell boundaries in one group of cells. However, the genes regulated by EMX2 in this context were previously not known. Using …

Infection Of Neonatal Mice With The Murine Norovirus Strain Wu23 Is A Robust Model To Study Norovirus Pathogenesis, Amy M Peiper, Emily W Helm, Quyen Nguyen, Matthew Phillips, Caroline G Williams, Dhairya Shah, Sarah Tatum, Neha Iyer, Marco Grodzki, Laura B Eurell, Aqsa Nasir, Megan T Baldridge, Stephanie M Karst

2020-Current year OA Pubs

Noroviruses are the leading cause of severe childhood diarrhea and foodborne disease worldwide. While they are a major cause of disease in all age groups, infections in the very young can be quite severe, with annual estimates of 50,000-200,000 fatalities in children under 5 years old. In spite of the remarkable disease burden associated with norovirus infections, very little is known about the pathogenic mechanisms underlying norovirus diarrhea, principally because of the lack of tractable small animal models. The development of the murine norovirus (MNV) model nearly two decades ago has facilitated progress in understanding host-norovirus interactions and norovirus strain …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Driver Mutations Dictate The Immunologic Landscape And Response To Checkpoint Immunotherapy Of Glioblastoma., Alan T Yeo, Rushil Shah, Konstantinos Aliazis, Rinku Pal, Tuoye Xu, Piyan Zhang, Shruti Rawal, Christopher M Rose, Frederick S Varn, Vicky A Appleman, Joon Yoon, Hemant Varma, Steven P Gygi, Roel G W Verhaak, Vassiliki A Boussiotis, Al Charest

Faculty Research 2023

The composition of the tumor immune microenvironment (TIME) is considered a key determinant of patients' response to immunotherapy. The mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) is a lethal primary brain cancer for which there are no curative treatments. GBMs are immunologically heterogeneous and impervious to checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models of GBM, we identified distinct immune landscapes associated with expression of EGFR wild-type and mutant EGFRvIII cancer driver mutations. Over time, accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) was more pronounced in EGFRvIII-driven GBMs and was correlated with resistance …

Sexual Dimorphism In Bidirectional Sr-Mitochondria Crosstalk In Ventricular Cardiomyocytes, Richard T Clements, Radmila Terentyeva, Shanna Hamilton, Paul M L Janssen, Karim Roder, Benjamin Y Martin, Fruzsina Perger, Timothy G Schneider, Zuzana Nichtova, Anindhya S Das, Roland Veress, Beth S Lee, Do-Gyoon Kim, Gideon Koren, Matthew S Stratton, György Csordás, Federica Accornero, Andriy E Belevych, Sandor Gyorke, Dmitry Terentyev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca²⁺ release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca²⁺] and produce less reactive oxygen species (ROS) compared to males, without change in respiration capacity. We hypothesized that in female VCMs, more efficient electron transport chain (ETC) organization into supercomplexes offsets the deficit in mito-Ca²⁺ accumulation, thereby reducing ROS production and stress-induced intracellular Ca²⁺ mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca²⁺] in female rat VCMs challenged …

Reduction Of Paraoxonase Expression Followed By Inactivation Across Independent Semiaquatic Mammals Suggests Stepwise Path To Pseudogenization., Allie M Graham, Jerrica M Jamison, Marisol Bustos, Charlotte Cournoyer, Alexa Michaels, Jason S Presnell, Rebecca Richter, Daniel E Crocker, Ari Fustukjian, Margaret E Hunter, Lorrie D Rea, Judit Marsillach, Clement E Furlong, Wynn K Meyer, Nathan L Clark

Faculty Research 2023

Convergent adaptation to the same environment by multiple lineages frequently involves rapid evolutionary change at the same genes, implicating these genes as important for environmental adaptation. Such adaptive molecular changes may yield either change or loss of protein function; loss of function can eliminate newly deleterious proteins or reduce energy necessary for protein production. We previously found a striking case of recurrent pseudogenization of the Paraoxonase 1 (Pon1) gene among aquatic mammal lineages-Pon1 became a pseudogene with genetic lesions, such as stop codons and frameshifts, at least four times independently in aquatic and semiaquatic mammals. Here, we assess the landscape …

A Multi-Lab Experimental Assessment Reveals That Replicability Can Be Improved By Using Empirical Estimates Of Genotype-By-Lab Interaction., Iman Jaljuli, Neri Kafkafi, Eliezer Giladi, Ilan Golani, Illana Gozes, Elissa J Chesler, Molly A. Bogue, Yoav Benjamini

Faculty Research 2023

The utility of mouse and rat studies critically depends on their replicability in other laboratories. A widely advocated approach to improving replicability is through the rigorous control of predefined animal or experimental conditions, known as standardization. However, this approach limits the generalizability of the findings to only to the standardized conditions and is a potential cause rather than solution to what has been called a replicability crisis. Alternative strategies include estimating the heterogeneity of effects across laboratories, either through designs that vary testing conditions, or by direct statistical analysis of laboratory variation. We previously evaluated our statistical approach for estimating …

Interleukin-33 Facilitates Liver Regeneration Through Serotonin-Involved Gut-Liver Axis, Yankai Wen, Christoph Emontzpohl, Long Xu, Constance L Atkins, Jong-Min Jeong, Yang Yang, Kangho Kim, Chuan Wu, Shizuo Akira, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms.

APPROACH AND RESULTS: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be …

Immune Profiling Of Adeno-Associated Virus Response Identifies B Cell-Specific Targets That Enable Vector Re-Administration In Mice, Maria Chen, Boram Kim, Maria I Jarvis, Samantha Fleury, Shuyun Deng, Shirin Nouraein, Susan Butler, Sangsin Lee, Courtney Chambers, H Courtney Hodges, Jerzy O Szablowski, Junghae Suh, Omid Veiseh

Faculty, Staff and Students Publications

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector …

N-Terminal Egfp-Tagging Of Rabbit Apolipoprotein A-I Decreases Expression And Impairs Cholesterol-Efflux Activity, Bradley K Wacker, Lianxiang Bi, Li Liu, Mary G Sorci-Thomas, Philip Ng, Donna J Palmer, Chongren Tang, David A Dichek

Faculty, Staff and Students Publications

No abstract provided.

Differential Regulation Of Cardiac Sodium Channels By Intracellular Fibroblast Growth Factors, Paweorn Angsutararux, Amal K Dutta, Martina Marras, Carlota Abella, Rebecca L Mellor, Jingyi Shi, Jeanne M Nerbonne, Jonathan R Silva

2020-Current year OA Pubs

Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant NaV1.5 α subunit is composed of four homologous repeats (I-IV) and forms a macromolecular complex with multiple accessory proteins, including intracellular fibroblast growth factors (iFGF). In spite of high homology, each of the iFGFs, iFGF11-iFGF14, as well as the individual iFGF splice variants, differentially regulates NaV channel gating, and the mechanisms underlying these differential effects remain elusive. Much of the work exploring iFGF regulation of NaV1.5 has been performed in mouse and rat ventricular myocytes in which iFGF13VY is the predominant …

Molecular Identity Changes Of Tumor-Associated Macrophages And Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening In A Mouse Glioblastoma Model, Yanrong Zhang, Jing Wang, Sara Natasha Ghobadi, Haiyan Zhou, Ai Huang, Marco Gerosa, Qingyi Hou, Olivier Keunen, Anna Golebiewska, Frezghi G Habte, Gerald A Grant, Ramasamy Paulmurugan, Kevin S Lee, Max Wintermark

Faculty, Staff and Student Publications

An orthotopically allografted mouse GL26 glioma model (Ccr2^RFP/wt-Cx3cr1^GFP/wt) was used to evaluate the effect of transient, focal opening of the Blood Brain Barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB Opening was induced by Magnetic Resonance Imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not show significant changes in cell numbers when compared to tumors in animals not receiving FUS. However, tumors that received two or three sessions …

Expanded Directly Binds Conserved Regions Of Fat To Restrain Growth Via The Hippo Pathway, Alexander D Fulford, Leonie Enderle, Jannette Rusch, Didier Hodzic, Maxine V Holder, Alex Earl, Robin Hyunseo Oh, Nicolas Tapon, Helen Mcneill

2020-Current year OA Pubs

The Hippo pathway is a conserved and critical regulator of tissue growth. The FERM protein Expanded is a key signaling hub that promotes activation of the Hippo pathway, thereby inhibiting the transcriptional co-activator Yorkie. Previous work identified the polarity determinant Crumbs as a primary regulator of Expanded. Here, we show that the giant cadherin Fat also regulates Expanded directly and independently of Crumbs. We show that direct binding between Expanded and a highly conserved region of the Fat cytoplasmic domain recruits Expanded to the apicolateral junctional zone and stabilizes Expanded. In vivo deletion of Expanded binding regions in Fat causes …

Abrogation Of Map4k4 Protein Function Causes Congenital Anomalies In Humans And Zebrafish, Victoria Patterson, Dorothy K Grange, Et Al.

2020-Current year OA Pubs

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Miceb, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …