Digital Commons Network^™

Phds/Cpt1b/Vdac1 Axis Regulates Long-Chain Fatty Acid Oxidation In Cardiomyocytes, Aude Angelini, Pradip K Saha, Antrix Jain, Sung Yun Jung, Randall L Mynatt, Xinchun Pi, Liang Xie

Faculty, Staff and Students Publications

Cardiac metabolism is a high-oxygen-consuming process, showing a preference for long-chain fatty acid (LCFA) as the fuel source under physiological conditions. However, a metabolic switch (favoring glucose instead of LCFA) is commonly reported in ischemic or late-stage failing hearts. The mechanism regulating this metabolic switch remains poorly understood. Here, we report that loss of PHD2/3, the cellular oxygen sensors, blocks LCFA mitochondria uptake and β-oxidation in cardiomyocytes. In high-fat-fed mice, PHD2/3 deficiency improves glucose metabolism but exacerbates the cardiac defects. Mechanistically, we find that PHD2/3 bind to CPT1B, a key enzyme of mitochondrial LCFA uptake, promoting CPT1B-P295 hydroxylation. Further, we …

Bias Of The Immune Response To Pneumocystis Murina Does Not Alter The Ability Of Neonatal Mice To Clear The Infection, Cathryn J. Kurkjian, Melissa L. Hollifield, David J. Feola, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Newborn mice are unable to clear Pneumocystis (PC) infection with the same efficiency as adults due, in part, to their inability to develop a robust immune response to infection until three weeks of age. It is known that infants tend develop a Th2 skewed response to antigen so we sought to determine whether a biased cytokine response altered the clearance of PC infection in neonatal mice. P. murina infection in neonatal mice resulted in increased IL-4 expression by CD4 T cells and myeloid cells, augmented IL-13 secretion within the airways and increased arginase activity in the airways, indicative of Th2-type …

Tet2 And Dnmt3a Mutations Exert Divergent Effects On Dna Repair And Sensitivity Of Leukemia Cells To Parp Inhibitors, Silvia Maifrede, Bac Viet Le, Margaret Nieborowska-Skorska, Konstantin Golovine, Katherine Sullivan-Reed, Wangisa M B Dunuwille, Joseph Nacson, Michael Hulse, Kelsey Keith, Jozef Madzo, Lisa Beatrice Caruso, Zachary Gazze, Zhaorui Lian, Antonella Padella, Kumaraswamy N. Chitrala, Boris A. Bartholdy, Ksenia Matlawska-Wasowska, Daniela Di Marcantonio, Giorgia Simonetti, Georg Greiner, Stephen M Sykes, Peter Valent, Elisabeth M. Paietta, Martin S. Tallman, Hugo F. Fernandez, Mark R. Litzow, Mark D. Minden, Jian Huang, Giovanni Martinelli, George S. Vassiliou, Italo Tempera, Katarzyna Piwocka, Neil Johnson, Grant A. Challen, Tomasz Skorski

Pediatrics Research and Scholarship

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F , and MPLW515L , or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52 . Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK-mediated non-homologous …

Alveolar Socket Healing In 5-Lipoxygenase Knockout Aged Female Mice Treated Or Not With High Dose Of Zoledronic Acid, Ramez H Mahmoud, Claudia C Biguetti, Gustavo B Simionato, Isabela C Custódio, Raquel B P Silva, Marco A H Duarte, Leonardo P Faverani, Edilson Ervolino, Walid D Fakhouri, Mariza A Matsumoto

Faculty, Staff and Student Publications

This study investigated the role 5-lypoxigenase (5-LO) on alveolar socket healing in aged female mice treated with zoledronic acid (ZL). Forty 129/Sv female mice (64-68 weeks old), 20 wild type (WT) and 20 5-LO knockout (5LOKO) were equally distributed according to ZL treatment: WT Control, WT ZL, 5LOKO Control, and 5LOKO ZL. ZL groups were treated with an intraperitoneal injection of 250 µg/Kg of ZL, while controls were treated with saline. Treatments were administered once a week, starting four weeks before surgery for tooth extraction and until 7 and 21 days post-surgery. Mice were euthanized for a comprehensive microscopic analysis …

Structure Of Venezuelan Equine Encephalitis Virus In Complex With The Ldlrad3 Receptor, Katherine Basore, Hongming Ma, Natasha M Kafai, Samantha Mackin, Arthur S Kim, Christopher A Nelson, Michael S Diamond, Daved H Fremont

Open Access Publications

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)

A Transcriptomic And Epigenomic Cell Atlas Of The Mouse Primary Motor Cortex, Zizhen Yao, Hanqing Liu, Fangming Xie, Stephan Fischer, Xinxin Wang, Et Al

Open Access Publications

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain

Clinical Trial And Postmarketing Safety Of Onasemnogene Abeparvovec Therapy, John W Day, Jerry R Mendell, Eugenio Mercuri, Richard S Finkel, Kevin A Strauss, Aaron Kleyn, Sitra Tauscher-Wisniewski, Francis Fonyuy Tukov, Sandra P Reyna, Deepa H Chand

2020-Current year OA Pubs

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign …

Cellular Regeneration As A Potential Strategy To Treat Cardiac Conduction Disorders, Satadru K Lahiri, Mohit M Hulsurkar, Xander Ht Wehrens

Faculty, Staff and Students Publications

Loss of atrioventricular conduction system (AVCS) cells due to either inherited or acquired deficits leads to conduction diseases, which can deteriorate into fatal cardiac arrhythmias and sudden death. In this issue of the JCI, Wang et al. constructed a mouse model of atrioventricular block (AVB) by inducing AVCS cell-specific injury using the Cx30.2 enhancer to drive expression of diphtheria toxin fragment A. AVCS cell ablation in adult mice led to irreversible AVB. jkjkIn contrast, AVCS cell injury in neonatal mice was followed by spontaneous recovery in a subset of mice, revealing a limited postnatal time window during which the regeneration …

Neuron-Specific Mitochondrial Oxidative Stress Results In Epilepsy, Glucose Dysregulation And A Striking Astrocyte Response, Ruth E Fulton, Jennifer N Pearson-Smith, Christopher Q Huynh, Timothy Fabisiak, Li-Ping Liang, Stefanos Aivazidis, Brigit A High, Georgia Buscaglia, Timothy Corrigan, Robert Valdez, Takahiko Shimizu, Manisha N Patel

Faculty, Staff and Students Publications

Mitochondrial superoxide (O2.−) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2.− to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative …

Rare Variants In Kdr, Encoding Vegf Receptor 2, Are Associated With Tetralogy Of Fallot., Doris Škorić-Milosavljević, Najim Lahrouchi, Fernanda M. Bosada, Gregor Dombrowsky, Simon G. Williams, Robert Lesurf, Fleur V Y Tjong, Roddy Walsh, Ihssane El Bouchikhi, Jeroen Breckpot, Enrique Audain, Aho Ilgun, Leander Beekman, Ilham Ratbi, Alanna Strong, Maximilian Muenke, Solveig Heide, Alison M. Muir, Mariam Hababa, Laura A. Cross, Dihong Zhou, T Pastinen, German Competence Network For Congenital Heart Defects, Elaine Zackai, Samir Atmani, Karim Ouldim, Najlae Adadi, Katharina Steindl, Anita Rauch, David Brook, Anna Wilsdon, Irene Kuipers, Nico A. Blom, Barbara J. Mulder, Heather C. Mefford, Boris Keren, Pascal Joset, Paul Kruszka, Isabelle Thiffault, Sarah E. Sheppard, Amy Roberts, Elisabeth M. Lodder, Bernard D. Keavney, Sally-Ann B. Clur, Seema Mital, Marc-Philip Hitz, Vincent M. Christoffels, Alex V. Postma, Connie R. Bezzina

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in …

Mutation Of The Epha2 Tyrosine-Kinase Domain Dysregulates Cell Pattern Formation And Cytoskeletal Gene Expression In The Lens, Yuefang Zhou, Thomas M Bennett, Philip A Ruzycki, Alan Shiels

Open Access Publications

Genetic variations in ephrin type-A receptor 2 (EPHA2) have been associated with inherited and age-related forms of cataract in humans. Here, we have characterized the eye lens phenotype and transcript profile of germline

Gut Microbiota-Derived Short-Chain Fatty Acids Protect Against The Progression Of Endometriosis, Sangappa B Chadchan, Pooja Popli, Chandrasekhar R Ambati, Eric Tycksen, Sang Jun Han, Serdar E Bulun, Nagireddy Putluri, Scott W Biest, Ramakrishna Kommagani

2020-Current year OA Pubs

Worldwide, ∼196 million are afflicted with endometriosis, a painful disease in which endometrial tissue implants and proliferates on abdominal peritoneal surfaces. Theories on the origin of endometriosis remained inconclusive. Whereas up to 90% of women experience retrograde menstruation, only 10% develop endometriosis, suggesting that factors that alter peritoneal environment might contribute to endometriosis. Herein, we report that whereas some gut bacteria promote endometriosis, others protect against endometriosis by fermenting fiber to produce short-chain fatty acids. Specifically, we found that altered gut microbiota drives endometriotic lesion growth and feces from mice with endometriosis contained less of short-chain fatty acid and n-butyrate …

Genetic Characterization, Current Model Systems And Prognostic Stratification In Pax Fusion-Negative Vs. Pax Fusion-Positive Rhabdomyosarcoma, Carina A Dehner, Amy E Armstrong, Marielle Yohe, Jack F Shern, Angela C Hirbe

Open Access Publications

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (

Cxcl17 Is Dispensable During Hypervirulent Mycobacterium Tuberculosis Hn878 Infection In Mice, José Alberto Choreño-Parra, Micah D Dunlap, Rosemary Swanson, Luis A Jiménez-Álvarez, Marcela Muñoz-Torrico, Silvia Guzmán-Beltrán, Joaquín Zúñiga, Shabaana A Khader

2020-Current year OA Pubs

CXCL17 is a novel mucosal chemokine that mediates myeloid cell recruitment and bactericidal activity and highly expressed in the respiratory tract. However, its role in tuberculosis (TB) immunopathogenesis or protection remains unknown. In this study, we evaluated the function of CXCL17 in a mouse model of aerosol infection with the clinical W-Beijing lineage

Identification Of Micrornas And Gene Regulatory Networks In Cleft Lip Common In Humans And Mice, Hiroki Yoshioka, Aimin Li, Akiko Suzuki, Sai Shankar Ramakrishnan, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

The etiology of cleft lip with/without cleft palate (CL/P), one of the most frequent craniofacial birth defects worldwide, is complicated by contributions of both genetic and environmental factors. Understanding the etiology of these conditions is essential for developing preventive strategies. This study thus aims to identify regulatory networks of microRNAs (miRNAs), transcriptional factors (TFs) and non-TF genes associated with cleft lip (CL) that are conserved in humans and mice. Notably, we found that miR-27b, miR-133b, miR-205, miR-376b and miR-376c were involved in the regulation of CL-associated gene expression in both humans and mice. Among the candidate miRNAs, the overexpression of …

Predilection For Developing A Hematogenous Orthopaedic Implant-Associated Infection In Older Versus Younger Mice, John M Thompson, Alyssa G Ashbaugh, Yu Wang, Robert J Miller, Julie E Pickett, Daniel L J Thorek, Robert S Sterling, Lloyd S Miller

2020-Current year OA Pubs

BACKGROUND: The pathogenesis of hematogenous orthopaedic implant-associated infections (HOIAI) remains largely unknown, with little understanding of the influence of the physis on bacterial seeding. Since the growth velocity in the physis of long bones decreases during aging, we sought to evaluate the role of the physis on influencing the development of Staphylococcus aureus HOIAI in a mouse model comparing younger versus older mice.

METHODS: In a mouse model of HOIAI, a sterile Kirschner wire was inserted retrograde into the distal femur of younger (5-8-week-old) and older (14-21-week-old) mice. After a 3-week convalescent period, a bioluminescent Staphylococcus aureus strain was inoculated …

Ankyrin-Dependent Na+ Channel Clustering Prevents Neuromuscular Synapse Fatigue, Chuansheng Zhang, Abhijeet Joshi, Yanhong Liu, Ozlem Sert, Seth G Haddix, Lindsay H Teliska, Anne Rasband, George G Rodney, Matthew N Rasband

Faculty, Staff and Students Publications

Skeletal muscle contraction depends on activation of clustered acetylcholine receptors (AchRs) and muscle-specific Na+ channels (Nav1.4). Some Nav1.4 channels are highly enriched at the neuromuscular junction (NMJ) and their clustering is thought to be essential for effective muscle excitation. However, this has not been experimentally tested, and how NMJ Na+ channels are clustered is unknown. Here, using muscle-specific AnkyrinR, AnkyrinB, and AnkyrinG single, double, and triple-conditional knockout mice we show that Nav1.4 channels fail to cluster only after deletion of all three ankyrins. Remarkably, ankyrin-deficient muscles have normal NMJ morphology, AchR clustering, sarcolemmal levels of Nav1.4, and muscle force, and …

Invariant Natural Killer T-Cell Subsets Have Diverse Graft-Versus-Host-Disease-Preventing And Antitumor Effects, Kristina Maas-Bauer, Juliane K Lohmeyer, Toshihito Hirai, Teresa Lopes Ramos, Furqan M Fazal, Ulrike M Litzenburger, Kathryn E Yost, Jessica V Ribado, Neeraja Kambham, Arielle S Wenokur, Po-Yu Lin, Maite Alvarez, Melissa Mavers, Jeanette Baker, Ami S Bhatt, Howard Y Chang, Federico Simonetta, Robert S Negrin

Faculty, Staff and Students Publications

Invariant natural killer T (iNKT) cells are a T-cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic graft-versus-host-disease (GVHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2, and iNKT17 sublineages, which differ transcriptomically and epigenomically and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GVHD is currently unknown. In this work, we generated highly purified murine iNKT sublineages, characterized their transcriptomic and epigenomic landscape, …

Transcriptional Network Involving Erg And Ar Orchestrates Distal-Less Homeobox-1 Mediated Prostate Cancer Progression, Sakshi Goel, Vipul Bhatia, Sushmita Kundu, Tanay Biswas, Shannon Carskadon, Nilesh S. Gupta, Mohammad Asim, Colm Morrissey, Nallasivam Palanisamy, Bushra Ateeq

Urology Articles

Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 …

The Concurrence Of Dna Methylation And Demethylation Is Associated With Transcription Regulation, Jiejun Shi, Jianfeng Xu, Yiling Elaine Chen, Jason Sheng Li, Ya Cui, Lanlan Shen, Jingyi Jessica Li, Wei Li

Children’s Nutrition Research Center Staff Publications

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. …

Endothelium-Specific Depletion Of Lrp1 Improves Glucose Homeostasis Through Inducing Osteocalcin, Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K Saha, Cristian Coarfa, Kimal Rajapakshe, Dimuthu Perera, Jizhong Cheng, Huaizhu Wu, Christie M Ballantyne, Zheng Sun, Liang Xie, Xinchun Pi

Faculty, Staff and Students Publications

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density …

Effect Of High Fat Diet On Body Weight, Visceral Fat Weight, And Pparg Expressions On Visceral Fat In Mice, Cantika Putri Melyana, Purwo Sri Rejeki, Sony Wibisono Mudjanarko, Lilik Herawati, Mohammad Anam Al-Arif

Folia Medica Indonesiana

Obesity becomes a global epidemic nowadays. The high-fat diet is used as an alternative therapy for obesity. The optimal composition of a high-fat diet to reduce body weight is still unknown. This study aimed to determine which components of a high-fat diet can decrease body weight, visceral fat, and PPARG expression of visceral fat. This study was conducted at the Faculty of Veterinary Medicine, Universitas Airlangga, for three months by using a randomized post-test only control group design. Fifty male mice, 2-3 months old, 18-30 grams were adapted for one week given standard diet AIN93-M, then mice were divided into …

Long-Term Treatment With Senolytic Drugs Dasatinib And Quercetin Ameliorates Age-Dependent Intervertebral Disc Degeneration In Mice, Emanuel J Novais, Victoria Tran, Shira N Johnston, Kayla R Darris, Alex J Roupas, Garrett A Sessions, Irving Shapiro, Brian O Diekman, Makarand V Risbud

Department of Orthopaedic Surgery Faculty Papers

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16INK4a, …

Functional Characterization Of T2d-Associated Snp Effects On Baseline And Er Stress-Responsive Β Cell Transcriptional Activation., Shubham Khetan, Susan Kales, Romy Kursawe, Alexandria Jillette, Jacob C Ulirsch, Steven K Reilly, Duygu Ucar, Ryan Tewhey, Michael L. Stitzel

Faculty Research 2021

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that …

Phagocytes Produce Prostaglandin E2 In Response To Cytosolic Listeria Monocytogenes, Courtney E. Mcdougal, Zachary T. Morrow, Tighe Christopher, Seonyoung Kim, Drake Carter, David M. Stevenson, Daniel Amador-Noguez, Mark J. Miller, John-Demian Sauer

Open Access Publications

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 …

Lipid-Nanoparticle-Encapsulated Mrna Vaccines Induce Protective Memory Cd8 T Cells Against A Lethal Viral Infection., Cory J Knudson, Pedro Alves-Peixoto, Hiromi Muramatsu, Colby Stotesbury, Lingjuan Tang, Paulo J C Lin, Ying K Tam, Drew Weissman, Norbert Pardi, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

It is well established that memory CD8 T cells protect susceptible strains of mice from mousepox, a lethal viral disease caused by ectromelia virus (ECTV), the murine counterpart to human variola virus. While mRNA vaccines induce protective antibody (Ab) responses, it is unknown whether they also induce protective memory CD8 T cells. We now show that immunization with different doses of unmodified or N(1)-methylpseudouridine-modified mRNA (modified mRNA) in lipid nanoparticles (LNP) encoding the ECTV gene EVM158 induced similarly strong CD8 T cell responses to the epitope TSYKFESV, albeit unmodified mRNA-LNP had adverse effects at the inoculation site. A single immunization …

Primary Osteoarthritis Early Joint Degeneration Induced By Endoplasmic Reticulum Stress Is Mitigated By Resveratrol, Jacqueline T Hecht, Alka C Veerisetty, Juliana Wu, Francoise Coustry, Mohammad G Hossain, Frankie Chiu, Francis H Gannon, Karen L Posey

Faculty, Staff and Student Publications

Increasing numbers of people are living with osteoarthritis (OA) due to aging and obesity, creating an urgent need for effective treatment and preventions. Two top risk factors for OA, age and obesity, are associated with endoplasmic reticulum (ER) stress. The I-ERS mouse, an ER stress-driven model of primary OA, was developed to study the role of ER stress in primary OA susceptibility. The I-ERS mouse has the unique ability to induce ER stress in healthy adult articular chondrocytes and cartilage, driving joint degeneration that mimics early primary OA. In this study, ER stress-induced damage occurred gradually and stimulated joint degeneration …

Endothelial Fgf Signaling Is Protective In Hypoxia-Induced Pulmonary Hypertension, Kel Vin Woo, Isabel Y Shen, Carla J Weinheimer, Attila Kovacs, Jessica Nigro, Chieh-Yu Lin, Murali Chakinala, Derek E Byers, David M Ornitz

Open Access Publications

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition …

Memory-Like Differentiation Enhances Nk Cell Responses To Melanoma, Nancy D Marin, Bradley A Krasnick, Michelle Becker-Hapak, Leah Conant, Simon P Goedegebuure, Melissa M Berrien-Elliott, Keenan J Robbins, Jennifer A Foltz, Mark Foster, Pamela Wong, Celia C Cubitt, Jennifer Tran, Christopher B Wetzel, Miriam Jacobs, Alice Y Zhou, David Russler-Germain, Lynne Marsala, Timothy Schappe, Ryan C Fields, Todd A Fehniger

Open Access Publications

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined.

EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK …

Exogenous Inter-Α Inhibitor Proteins Prevent Cell Death And Improve Ischemic Stroke Outcomes In Mice, Louise D Mccullough, Meaghan Roy-O'Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C Kraushaar, Anjali Chauhan, Lauren H Sansing, Barbara S Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

Faculty, Staff and Students Publications

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when …