Systems Biology Commons^™

Conditional Expression Of Tgf-Β1 In Skeletal Muscles Causes Endomysial Fibrosis And Myofibers Atrophy, Jigna Narola, Sachchida Nand Pandey, Adam Glick, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

To study the effects of transforming growth factor beta 1 (TGF-β1) on fibrosis and failure of regeneration of skeletal muscles, we generated a tet-repressible muscle-specific TGF-β1transgenic mouse in which expression of TGF-β1 is controlled by oral doxycycline. The mice developed muscle weakness and atrophy after TGF-β1 over-expression. We defined the group of mice that showed phenotype within 2 weeks as early onset (EO) and the rest as late onset (LO), which allowed us to further examine phenotypic differences between the groups. While only mice in the EO group showed significant muscle weakness, pathological changes including endomysial fibrosis and smaller …

Vbp15, A Novel Anti-Inflammatory And Membrane-Stabilizer, Improves Muscular Dystrophy Without Side Effects, Christopher R. Heier, Jesse M. Damsker, Qing Yu, Blythe C. Dillingham, Tony Huynh, Heather A. Gordish-Dressman, Jyoti K. Jaiswal, Eric P. Hoffman, Kanneboyina Nagaraju, +15 Additional Authors

Genomics and Precision Medicine Faculty Publications

Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. …

An Exploration Of Heat Tolerance In Mice Utilizing Mrna And Microrna Expression Analysis, Islam Aminul, Patricia A. Deuster, Joseph M. Devaney, Svetlana Ghimbovschi, Yifan Chen

Genomics and Precision Medicine Faculty Publications

Background

Individuals who rapidly develop hyperthermia during heat exposure (heat-intolerant) are vulnerable to heat associated illness and injury. We recently reported that heat intolerant mice exhibit complex alterations in stress proteins in response to heat exposure. In the present study, we further explored the role of genes and molecular networks associated with heat tolerance in mice.

Methodology

Heat-induced physiological and biochemical changes were assessed to determine heat tolerance levels in mice. We performed RNA and microRNA expression profiling on mouse gastrocnemius muscle tissue samples to determine novel biological pathways associated with heat tolerance.

Principal Findings

Mice (n = 18) were …

Individual Differences In Emotion-Cognition Interactions: Emotional Valence Interacts With Serotonin Transporter Genotype To Influence Brain Systems Involved In Emotional Reactivity And Cognitive Control, Melanie Stollstorff, Yuko Munakata, Arielle P.C. Jensen, Ryan M. Guild, Harry R. Smolker, Joseph M. Devaney, Marie T. Banich

Genomics and Precision Medicine Faculty Publications

The serotonin transporter gene (5-HTTLPR) influences emotional reactivity and attentional bias toward or away from emotional stimuli, and has been implicated in psychopathological states, such as depression and anxiety disorder. The short allele is associated with increased reactivity and attention toward negatively-valenced emotional information, whereas the long allele is associated with increased reactivity and attention towardpositively-valenced emotional information. The neural basis for individual differences in the ability to exert cognitive control over these bottom-up biases in emotional reactivity and attention is unknown, an issue investigated in the present study. Healthy adult participants were divided into two groups, either homozygous …

The Proton Pump Inhibitor Lansoprazole Improves The Skeletal Phenotype In Dystrophin Deficient Mdx Mice, Arpana Sali, Gina M. Many, Heather Gordish-Dressman, Jack Van Der Meulen, Aditi Phadke, Christopher F. Spurney, Avital Cnaan, Eric P. Hoffman, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

Background

In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology.

Methodology/Principal Findings

We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle …

Omigapil Treatment Decreases Fibrosis And Improves Respiratory Rate In Dy2j Mouse Model Of Congenital Muscular Dystrophy, Qing Yu, Arpana Sali, Jack Van Der Meulen, Brittany K. Creeden, Heather Gordish-Dressman, Anne Rutkowski, Sree Rayavarapu, Kitipong Uaesoontrachoon, Tony Huynh, Kanneboyina Nagaraju, Christopher F. Spurney

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Idiopathic Inflammatory Myopathies: Pathogenic Mechanisms Of Muscle Weakness, Sree Rayavarapu, William Coley, Travis B. Kinder, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

Idiopathic inflammatory myopathies (IIMs) are a heterogenous group of complex muscle diseases of unknown etiology. These diseases are characterized by progressive muscle weakness and damage, together with involvement of other organ systems. It is generally believed that the autoimmune response (autoreactive lymphocytes and autoantibodies) to skeletal muscle-derived antigens is responsible for the muscle fiber damage and muscle weakness in this group of disorders. Therefore, most of the current therapeutic strategies are directed at either suppressing or modifying immune cell activity. Recent studies have indicated that the underlying mechanisms that mediate muscle damage and dysfunction are multiple and complex. Emerging evidence …

Daily Supplementation Of D-Ribose Shows No Therapeutic Benefits In The Mhc-I Transgenic Mouse Model Of Inflammatory Myositis, William Coley, Sree Rayavarapu, Jack H. Van Der Meulen, Ayyappa S. Duba, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

Background

Current treatments for idiopathic inflammatory myopathies (collectively called myositis) focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, adenosine monophosphate deaminase (AMPD1), leads to muscle weakness in a mouse model of myositis and may provide a mechanistic …

Dux4 Differentially Regulates Transcriptomes Of Human Rhabdomyosarcoma And Mouse C2c12 Cells, Vishakha Sharma, Naoe Harafuji, Alexandra Belayew, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

Facioscapulohumeral muscular dystrophy (FSHD) is linked to the deletion of the D4Z4 arrays at chromosome 4q35. Recent studies suggested that aberrant expression of double homeobox 4 (DUX4) from the last D4Z4 repeat causes FSHD. The aim of this study is to determine transcriptomic responses to ectopically expressed DUX4 in human and mouse cells of muscle lineage. We expression profiled human rhabdomyosarcoma (RD) cells and mouse C2C12 cells transfected with expression vectors of DUX4 using the Affymetrix Human Genome U133 Plus 2.0 Arrays and Mouse Genome 430 2.0 Arrays, respectively. A total of 2267 and 150 transcripts were identified to be …

Human Cytomegalovirus Inhibits Apoptosis By Proteasome-Mediated Degradation Of Bax At Endoplasmic Reticulum-Mitochondrion Contacts, Aiping Zhang, Richard L. Hildreth, Anamaris M. Colberg-Poley

Genomics and Precision Medicine Faculty Publications

Human cytomegalovirus (HCMV) encodes the UL37 exon 1 protein (pUL37x1), which is the potent viral mitochondrion-localized inhibitor of apoptosis (vMIA), to increase survival of infected cells. HCMV vMIA traffics from the endoplasmic reticulum (ER) to ER subdomains, which are physically linked to mitochondria known as mitochondrion-associated membranes (MAM), and to mitochondria. The antiapoptotic function of vMIA is thought to primarily result from its ability to inhibit Bax-mediated permeabilization of the outer mitochondrial membrane (OMM). Here, we establish that vMIA retargets Bax to the MAM as well as to the OMM from immediate early through late times of infection. However, MAM …

Mir-411 Is Up-Regulated In Fshd Myoblasts And Suppresses Myogenic Factors, Naoe Harafuji, Peter Schneiderat, Maggie C. Walter, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

Background

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder, which is linked to the contraction of the D4Z4 array at chromosome 4q35. Recent studies suggest that this shortening of the D4Z4 array leads to aberrant expression of double homeobox protein 4 (DUX4) and causes FSHD. In addition, misregulation of microRNAs (miRNAs) has been reported in muscular dystrophies including FSHD. In this study, we identified a miRNA that is differentially expressed in FSHD myoblasts and investigated its function.

Methods

To identify misregulated miRNAs and their potential targets in FSHD myoblasts, we performed expression profiling of both miRNA and mRNA …

Pro-Asthmatic Cytokines Regulate Unliganded And Ligand-Dependent Glucocorticoid Receptor Signaling In Airway Smooth Muscle, Aihua Hu, Maureen B. Josephson, Barry L. Diener, Gustavo Nino, Shuyun Xu, Chinmay Paranjape, Jordan S. Orange, Michael M. Grunstein

Genomics and Precision Medicine Faculty Publications

To elucidate the regulation of glucocorticoid receptor (GR) signaling under pro-asthmatic conditions, cultured human airway smooth muscle (HASM) cells were treated with proinflammatory cytokines or GR ligands alone and in combination, and then examined for induced changes in ligand-dependent and -independent GR activation and downstream signaling events. Ligand stimulation with either cortisone or dexamethsone (DEX) acutely elicited GR translocation to the nucleus and, comparably, ligand-independent stimulation either with the Th2 cytokine, IL-13, or the pleiotropic cytokine combination, IL-1β/TNFα, also acutely evoked GR translocation. The latter response was potentiated by combined exposure of cells to GR ligand and cytokine. Similarly, treatment …

Nuclear Envelope Laminopathies: Evidence For Developmentally Inappropriate Chromatin-Nuclear Envelope Interactions, Jelena Perovanovic, Jyoti K. Jaiswal, Nikola Markovic, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

Background

During terminal differentiation of cells, there is typically a transition of the nuclear envelope from the Lamin B protein to Lamin A/C proteins. This is commensurate with exit from the cell cycle, and maintenance of the transcriptional programs associated with the terminally differentiated cells. Dominant missense mutations in Lamin A/C cause a broad spectrum of human genetic disorders, where specific point mutations are associated with defects in specific organs or tissues. We have previously presented a model where Lamin A/C mutations disrupt developmentally appropriate interactions between chromatin and the nuclear envelope and lead to poor coordination of E2F cell …

Dux4 Expression In Fshd Muscle Cells: How Could Such A Rare Protein Cause A Myopathy?, Alexandra Tassin, Dalila Laoudj-Chenivesse, Celine Vanderplanck, Marietta Barro, Sebastien Charron, Eugenie Ansseau, Yi-Wen Chen, Jacques Mercier, Frederique Coppee, Alexandra Belayew

Genomics and Precision Medicine Faculty Publications

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent hereditary muscle disorders. It is linked to contractions of the D4Z4 repeat array in 4q35. We have characterized the double homeobox 4 (DUX4) gene in D4Z4 and its mRNA transcribed from the distal D4Z4 unit to a polyadenylation signal in the flanking pLAM region. It encodes a transcription factor expressed in FSHD but not healthy muscle cells which initiates a gene deregulation cascade causing differentiation defects, muscle atrophy and oxidative stress.PITX1 was the first identified DUX4 target and encodes a transcription factor involved in muscle atrophy. DUX4 was …

Highlights From The Functional Single Nucleotide Polymorphisms Associated With Human Muscle Size And Strength Or Famuss Study, Linda S. Pescatello, Joseph M. Devaney, Monica J. Hubal, Paul D. Thompson, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

The purpose of the Functional Single Nucleotide Polymorphisms Associated with Human Muscle Size and Strength study or FAMuSS was to identify genetic factors that dictated the response of health-related fitness phenotypes to resistance exercise training (RT). The phenotypes examined were baseline muscle strength and muscle, fat, and bone volume and their response to RT. FAMuSS participants were 1300 young (24 years), healthy men (42%) and women (58%) that were primarily of European-American descent. They were genotyped for ~500 polymorphisms and completed the Paffenbarger Physical Activity Questionnaire to assess energy expenditure and time spent in light, moderate, and vigorous intensity habitual …

Extensive And Prolonged Restoration Of Dystrophin Expression With Vivo-Morpholino-Mediated Multiple Exon Skipping In Dystrophic Dogs, Toshifumi Yokota, Akinori Nakamura, Tetsuya Nagata, Takashi Saito, Masanori Kobayashi, Yoshitsugu Aoki, Yusuke Echigoya, Terence A. Partridge, Eric P. Hoffman, Shinichi Takeda

Genomics and Precision Medicine Faculty Publications

Duchenne muscular dystrophy (DMD) is a severe and the most prevalent form of muscular dystrophy, characterized by rapid progression of muscle degeneration. Antisense-mediated exon skipping is currently one of the most promising therapeutic options for DMD. However, unmodified antisense oligos such as morpholinos require frequent (weekly or bi-weekly) injections. Recently, new generation morpholinos such as vivo-morpholinos are reported to lead to extensive and prolonged dystrophin expression in the dystrophic mdx mouse, an animal model of DMD. The vivo-morpholino contains a cell-penetrating moiety, octa-guanidine dendrimer. Here, we sought to test the efficacy of multiple exon skipping of exons 6–8 with vivo-morpholinos …

Deletion Of Galectin-3 Exacerbates Microglial Activation And Accelerates Disease Progression And Demise In A Sod1 G93a Mouse Model Of Amyotrophic Lateral Sclerosis, Bruce J. Lerman, Eric P. Hoffman, Margaret L. Sutherland, Khaled Bouri, Daniel K. Hsu, Jeffrey D. Rothstein, Susan M. Knoblach

Genomics and Precision Medicine Faculty Publications

Galectins are pleiotropic carbohydrate-binding lectins involved in inflammation, growth/differentiation, and tissue remodeling. The functional role of galectins in amyotrophic lateral sclerosis (ALS) is unknown. Expression studies revealed increases in galectin-1 mRNA and protein in spinal cords from SOD1 ^G93A mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1^G93A mice and sporadic ALS patients. As the increase in galectin-3 appeared in early presymptomatic stages and increased progressively through to end stage of disease in the mouse, it was selected for additional study, where it was found to be mainly expressed by microglia. Galectin-3 antagonists …

Platelets Induce Apoptosis During Sepsis In A Contact-Dependent Manner That Is Inhibited By Gpiib/Iiia Blockade, Matthew Sharron, Claire E. Hoptay, Andrew A. Wiles, Lindsay M. Garvin, Mayya Geha, Angela S. Benton, Kanneboyina Nagaraju, Robert J. Freishtat

Genomics and Precision Medicine Faculty Publications

Purpose

End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis.

Methods

End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score.

Measurements and Main Results …

Conditional Over-Expression Of Pitx1 Causes Skeletal Muscle Dystrophy In Mice, Sachchida Nand Pandey, Jennifer Cabotage, Rongye Shi, Manjusha Dixit, Margaret L. Sutherland, Jian Liu, Stephanie Muger, Scott Q. Harper, Kanneboyina Nagaraju, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

Paired-like homeodomain transcription factor 1 (PITX1) was specifically up-regulated in patients with facioscapulohumeral muscular dystrophy (FSHD) by comparing the genome-wide mRNA expression profiles of 12 neuromuscular disorders. In addition, it is the only known direct transcriptional target of the double homeobox protein 4 (DUX4) of which aberrant expression has been shown to be the cause of FSHD. To test the hypothesis that up-regulation of PITX1 contributes to the skeletal muscle atrophy seen in patients with FSHD, we generated a tet-repressible muscle-specific Pitx1 transgenic mouse model in which expression of PITX1 in skeletal muscle can be controlled by oral administration of …

Il-6 Signaling Blockade Increases Inflammation But Does Not Affect Muscle Function In The Mdx Mouse, Mathew A. Kostek, Kanneboyina Nagaraju, Emidio E. Pistilli, Arpana Sali, San-Huei Lai, Brad Gordon, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Sphingosine-1-Phosphate Enhances Satellite Cell Activation In Dystrophic Muscles Through A S1pr2/Stat3 Signaling Pathway, Kenneth C. Loh, Weng-In Leong, Morgan E. Carlson, Babak Oskouian, Ashok Kumar, Henrik Fyrst, Meng Zhang, Richard L. Proia, Eric P. Hoffman, Julie D. Saba

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Analysis Of Large Phenotypic Variability Of Eec And Shfm4 Syndromes Caused By K193e Mutation Of The Tp63 Gene, Jianhua Wei, Yang Xue, Lian Wu, Jie Ma, Xiuli Yi, Junrui Zhang, Bin Lu, Chunying Li, Dashuang Shi, Songtao Shi, Xinghua Feng, Tao Cai

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Role Of Non-Immune Mechanisms Of Muscle Damage In Idiopathic Inflammatory Myopathies, William Coley, Sree Rayavarapu, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Glucocorticoid-Treated Mice Are An Inappropriate Positive Control For Long-Term Preclinical Studies In The Mdx Mouse, Arpana Sali, Alfredo D. Guerron, Heather Gordish-Dressman, Christopher F. Spurney, Micaela Iantorno, Eric P. Hoffman, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Family History Of Autoimmune Disease In Patients With Aicardi-Goutières Syndrome, Johanna L. Schmidt, Ivana Olivieri, Jodie M. Vento, Elisa Fazzi, Heather A. Gordish-Dressman, Simona Orcesi, Adeline Vanderver

Genomics and Precision Medicine Faculty Publications

PURPOSE: The purpose of this study was to explore anecdotal evidence for an increase in the prevalence of autoimmune diseases in family members of patients with Aicardi-Goutières syndrome (AGS).

METHODS: Pedigrees of patients and controls were analyzed using chi-square and logistic regression to assess differences in reports of autoimmune disease among family members of cases and controls. Data was collected at Children's National Medical Center in Washington, DC, USA and at the International Aicardi-Goutières Syndrome Association Scientific Headquarters, C. Mondino National Institute of Neurology in Pavia, Italy.

RESULTS: The number of individuals with reported autoimmune disease is significantly related to …

Phylogenetic Search Through Partial Tree Mixing., Kenneth Sundberg, Mark Clement, Quinn Snell, Dan Ventura, Michael Whiting, Keith Crandall

Computational Biology Institute

BACKGROUND: Recent advances in sequencing technology have created large data sets upon which phylogenetic inference can be performed. Current research is limited by the prohibitive time necessary to perform tree search on a reasonable number of individuals. This research develops new phylogenetic algorithms that can operate on tens of thousands of species in a reasonable amount of time through several innovative search techniques.

RESULTS: When compared to popular phylogenetic search algorithms, better trees are found much more quickly for large data sets. These algorithms are incorporated in the PSODA application available at http://dna.cs.byu.edu/psoda

CONCLUSIONS: The use of Partial Tree Mixing …

Eps Homology Domain Endosomal Transport Proteins Differentially Localize To The Neuromuscular Junction, Suzanne E. Mate, Jack H. Van Der Meulen, Priyanka Arya, Sohinee Bhattacharyya, Hamid Band, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

No abstract provided.