Systems Biology Commons^™

The Treat-Nmd Advisory Committee For Therapeutics (Tact): An Innovative De-Risking Model To Foster Orphan Drug Development., Emma Heslop, Cristina Csimma, Volker Straub, John Mccall, Kanneboyina Nagaraju, Kathryn R. Wagner, Didier Caizergues, Rudolf Korinthenberg, Kevin M. Flanigan, Petra Kaufmann, Elizabeth Mcneil, Jerry Mendell, Sharon Hesterlee, Dominic J. Wells, Kate Bushby

Genomics and Precision Medicine Faculty Publications

Despite multiple publications on potential therapies for neuromuscular diseases (NMD) in cell and animal models only a handful reach clinical trials. The ability to prioritise drug development according to objective criteria is particularly critical in rare diseases with large unmet needs and a limited numbers of patients who can be enrolled into clinical trials. TREAT-NMD Advisory Committee for Therapeutics (TACT) was established to provide independent and objective guidance on the preclinical and development pathway of potential therapies (whether novel or repurposed) for NMD.We present our experience in the establishment and operation of the TACT. TACT provides a unique resource of …

Genetic Modifiers Of Ambulation In The Cinrg Duchenne Natural History Study., Luca Bello, Akanchha Kesari, Heather A. Gordish-Dressman, Avital Cnaan, Lauren P Morgenroth, Jaya Punetha, Tina Duong, Erik Henricson, Elena Pegoraro, Craig M. Mcdonald, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Tyrosine 705 Phosphorylation Of Stat3 Is Associated With Phenotype Severity In Tgfβ1 Transgenic Mice, Eleonora Guadagnin, Jigna Narola, Carsten G. Bonnemann, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

Transforming growth factor beta 1 (TGFβ1) is a key player in skeletal muscle degenerative and regenerative processes. We previously showed that conditionally overexpressing TGFβ1 in skeletal muscles caused myofiber atrophy and endomysial fibrosis in mice. However, the disease severity varied significantly among individual mice. While 40% of mice developed severe muscle pathology and lost body weight within 2 weeks of TGFβ1 transgene induction in muscles, the rest showed milder or no phenotype. This study aims at determining whether signal transducer and activator of transcription 3 (STAT3) plays a role in the phenotypic difference and whether it can be activated by …

An Analysis Of Dna Methylation In Human Adipose Tissue Reveals Differential Modification Of Obesity Genes Before And After Gastric Bypass And Weight Loss, Miles C. Benton, Alice Johnstone, David Eccles, Brennan Harmon, Mark T. Hayes, Rod A. Lea, Lyn Griffiths, Eric P. Hoffman, Richard S. Stubbs, Donia Macartney-Coxson

Genomics and Precision Medicine Faculty Publications

Background

Environmental factors can influence obesity by epigenetic mechanisms. Adipose tissue plays a key role in obesity-related metabolic dysfunction, and gastric bypass provides a model to investigate obesity and weight loss in humans.

Results

Here, we investigate DNA methylation in adipose tissue from obese women before and after gastric bypass and significant weight loss. In total, 485,577 CpG sites were profiled in matched, before and after weight loss, subcutaneous and omental adipose tissue. A paired analysis revealed significant differential methylation in omental and subcutaneous adipose tissue. A greater proportion of CpGs are hypermethylated before weight loss and increased methylation is …

Culture Conditions Affect Expression Of Dux4 In Fshd Myoblasts, Sachchida Nand Pandey, Hunain Khawaja, Yi-Wen Chen

Genomics and Precision Medicine Faculty Publications

Facioscapulohumeral muscular dystrophy (FSHD) is believed to be caused by aberrant expression of double homeobox 4 (DUX4) due to epigenetic changes of the D4Z4 region at chromosome 4q35. Detecting DUX4 is challenging due to its stochastic expression pattern and low transcription level. In this study, we examined different cDNA synthesis strategies and the sensitivity for DUX4 detection. In addition, we investigated the effects of dexamethasone and knockout serum replacement (KOSR) on DUX4 expression in culture. Our data showed that DUX4 was consistently detected in cDNA samples synthesized using Superscript III. The sensitivity of DUX4 detection was higher in the samples …

The N-Acetylglutamate Synthase Family: Structures, Function And Mechanisms, Dashuang Shi, Norma M. Allewell, Mendel Tuchman

Genomics and Precision Medicine Faculty Publications

N-acetylglutamate synthase (NAGS) catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and L-glutamate. In microorganisms and plants, the enzyme functions in the arginine biosynthetic pathway, while in mammals, its major role is to produce the essential co-factor of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle. Recent work has shown that several different genes encode enzymes that can catalyze NAG formation. A bifunctional enzyme was identified in certain bacteria, which catalyzes both NAGS and N-acetylglutamate kinase (NAGK) activities, the first two steps of the arginine biosynthetic pathway. Interestingly, these bifunctional enzymes have higher sequence similarity to vertebrate NAGS than …

Muscular Dystrophy In The Mdx Mouse Is A Severe Myopathy Compounded By Hypotrophy, Hypertrophy And Hyperplasia., William Duddy, Stephanie Duguez, Helen Johnston, Tatiana V. Cohen, Aditi Phadke, Heather Gordish-Dressman, Kanneboyina Nagaraju, Viola Gnocchi, Siewhui Low, Terence Partridge

Genomics and Precision Medicine Faculty Publications

Background

Preclinical testing of potential therapies for Duchenne muscular dystrophy (DMD) is conducted predominantly of the mdx mouse. But lack of a detailed quantitative description of the pathology of this animal limits our ability to evaluate the effectiveness of putative therapies or their relevance to DMD.

Methods

Accordingly, we have measured the main cellular components of muscle growth and regeneration over the period of postnatal growth and early pathology in mdx and wild-type (WT) mice; phalloidin binding is used as a measure of fibre size, myonuclear counts and BrdU labelling as records of myogenic activity.

Results

We confirm a two-phase …

The Actn3 R577x Polymorphism Is Associated With Cardiometabolic Fitness In Healthy Young Adults., Chelsea L Deschamps, Kimberly E Connors, Matthias S Klein, Virginia L Johnsen, Jane Shearer, Hans J Vogel, Joseph M. Devaney, Heather Gordish-Dressman, Gina M Many, Whitney Barfield, Eric P. Hoffman, William E Kraus, Dustin S Hittel

Genomics and Precision Medicine Faculty Publications

Homozygosity for a premature stop codon (X) in the ACTN3 “sprinter” gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 ± 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 ± 1.5 vs …

Upregulated Il-1Β In Dysferlin-Deficient Muscle Attenuates Regeneration By Blunting The Response To Pro-Inflammatory Macrophages., Tatiana V. Cohen, Gina M. Many, Bryan D. Fleming, Viola F. Gnocchi, Svetlana Ghimbovschi, David M. Mosser, Eric P. Hoffman, Terence A. Partridge

Genomics and Precision Medicine Faculty Publications

BACKGROUND: Loss-of-function mutations in the dysferlin gene (DYSF) result in a family of muscle disorders known collectively as the dysferlinopathies. Dysferlin-deficient muscle is characterized by inflammatory foci and macrophage infiltration with subsequent decline in muscle function. Whereas macrophages function to remove necrotic tissue in acute injury, their prevalence in chronic myopathy is thought to inhibit resolution of muscle regeneration. Two major classes of macrophages, classical (M1) and alternative (M2a), play distinct roles during the acute injury process. However, their individual roles in chronic myopathy remain unclear and were explored in this study.

METHODS: To test the roles of the two …

From Genome To Structure And Back Again: A Family Portrait Of The Transcarbamylases., Dashuang Shi, Norma M. Allewell, Mendel Tuchman

Genomics and Precision Medicine Faculty Publications

No abstract provided.

Transcriptional Pathways Associated With Skeletal Muscle Changes After Spinal Cord Injury And Treadmill Locomotor Training., Celine Baligand, Yi-Wen Chen, Fan Ye, Sachchida Nand Pandey, San-Huei Lai, Min Liu, Krista Vandenborne

Genomics and Precision Medicine Faculty Publications

The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and …

Elusive Sources Of Variability Of Dystrophin Rescue By Exon Skipping., Maria Candida Vila, Margaret Benny Klimek, James S Novak, Sree Rayavarapu, Kitipong Uaesoontrachoon, Jessica F Boehler, Heather Gordish-Dressman, Terence A Partridge, Kristy J. Brown, Yetrib Hathout, John Van Den Anker, Eric P. Hoffman, Kanneboyina Nagaraju, +7 Additional Authors

Genomics and Precision Medicine Faculty Publications

BACKGROUND: Systemic delivery of anti-sense oligonucleotides to Duchenne muscular dystrophy (DMD) patients to induce de novo dystrophin protein expression in muscle (exon skipping) is a promising therapy. Treatment with Phosphorodiamidate morpholino oligomers (PMO) lead to shorter de novo dystrophin protein in both animal models and DMD boys who otherwise lack dystrophin; however, restoration of dystrophin has been observed to be highly variable. Understanding the factors causing highly variable induction of dystrophin expression in pre-clinical models would likely lead to more effective means of exon skipping in both pre-clinical studies and human clinical trials.

METHODS: In the present study, we investigated …

Annexin A1 Deficiency Does Not Affect Myofiber Repair But Delays Regeneration Of Injured Muscles., Evgenia Leikina, Aurelia Defour, Kamran Melikov, Jack H Van Der Meulen, Kanneboyina Nagaraju, Shivaprasad Bhuvanendran, Claudia Gebert, Karl Pfeifer, Leonid V. Chernomordik, Jyoti K. Jaiswal

Genomics and Precision Medicine Faculty Publications

Repair and regeneration of the injured skeletal myofiber involves fusion of intracellular vesicles with sarcolemma and fusion of the muscle progenitor cells respectively. In vitro experiments have identified involvement of Annexin A1 (Anx A1) in both these fusion processes. To determine if Anx A1 contributes to these processes during muscle repair in vivo, we have assessed muscle growth and repair in Anx A1-deficient mouse (AnxA1-/-). We found that the lack of Anx A1 does not affect the muscle size and repair of myofibers following focal sarcolemmal injury and lengthening contraction injury. However, the lack of Anx A1 delayed muscle regeneration …

Genetic Modifiers Of Duchenne Muscular Dystrophy And Dilated Cardiomyopathy., Andrea Barp, Luca Bello, Luisa Politano, Paola Melacini, Chiara Calore, Eric P. Hoffman, +16 Additional Authors

Genomics and Precision Medicine Faculty Publications

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.

METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as …

Transcriptional Pathways Associated With Skeletal Muscle Changes After Spinal Cord Injury And Treadmill Locomotor Training., Celine Baligand, Yi-Wen Chen, Fan Ye, Sachchida Nand Pandey, San-Huei Lai, Min Liu, Krista Vandenborne

Genomics and Precision Medicine Faculty Publications

The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and …

High Rates Of Hiv Seroconversion In Pregnant Women And Low Reported Levels Of Hiv Testing Among Male Partners In Southern Mozambique: Results From A Mixed Methods Study, Caroline De Schacht, Heather J. Hoffman, Nedio Mabunda, Carlota Lucas, Catharina L. Alons, Ana Madonela, Adolfo Vubil, Orlando C. Ferreira, Nurbai Calu, Iolanda S. Santos, Ilesh V. Jani, Laura Guay

Genomics and Precision Medicine Faculty Publications

Introduction

Prevention of acute HIV infections in pregnancy is required to achieve elimination of pediatric HIV. Identification and support for HIV negative pregnant women and their partners, particularly serodiscordant couples, are critical. A mixed method study done in Southern Mozambique estimated HIV incidence during pregnancy, associated risk factors and factors influencing partner's HIV testing.

Methods

Between April 2008 and November 2011, a prospective cohort of 1230 HIV negative pregnant women was followed during pregnancy. A structured questionnaire, HIV testing, and collection of dried blood spots were done at 2–3 scheduled visits. HIV incidence rates were calculated by repeat HIV testing …

Whole Exome Sequencing In Family Trios Reveals De Novo Mutations In Pura As A Cause Of Severe Neurodevelopmental Delay And Learning Disability, David Hunt, Richard J. Leventer, Cas Simons, Ryan J. Taft, Kathryn J. Swoboda, Mary Gawne-Cain, Alex C. Magee, Perter D. Turnpenny, Diana Baralle

Genomics and Precision Medicine Faculty Publications

Background De novo mutations are emerging as an important cause of neurocognitive impairment, and whole exome sequencing of case-parent trios is a powerful way of detecting them. Here, we report the findings in four such trios.

Methods The Deciphering Developmental Disorders study is using whole exome sequencing in family trios to investigate children with severe, sporadic, undiagnosed developmental delay. Three of our patients were ascertained from the first 1133 children to have been investigated through this large-scale study. Case 4 was a phenotypically isolated case recruited into an undiagnosed rare disorders sequencing study.

Results Protein-altering de novo mutations in PURA …

Affinity Proteomics Within Rare Diseases: A Bio‐Nmd Study For Blood Biomarkers Of Muscular Dystrophies, Brucu Ayoglu, Amina Chaouch, Hans Lochmuller, Luisa Politano, Enrico Bertini, Sebahattin Cirak, +17 Additional Authors

Genomics and Precision Medicine Faculty Publications

Despite the recent progress in the broad‐scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO‐NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven …

Asynchronous Remodeling Is A Driver Of Failed Regeneration In Duchenne Muscular Dystrophy, Sherry Dadgar, Zuyi Wang, Helen Johnston, Akanchha Kesari, Kanneboyina Nagaraju, Yi-Wen Chen, D. Ashley Hill, Terence A. Partridge, Robert J. Freishtat, Javad Nazarian, Jianhua Xuan, Yue Wang, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are …

Rapid Identification Of A Novel Complex I Mt-Nd2 M.10134c>A Mutation In A Leigh Syndrome Patient, David K. Miller, Minal J. Menezes, Cas Simons, Lisa G. Riley, Sandra T. Cooper, Sean M. Grimmond, David R. Thorburn, John Christodoulou, Ryan J. Taft

Genomics and Precision Medicine Faculty Publications

Leigh syndrome (LS) is a rare progressive multi-system neurodegenerative disorder, the genetics of which is frequently difficult to resolve. Rapid determination of the genetic etiology of LS in a 5-year-old girl facilitated inclusion in Edison Pharmaceutical’s phase 2B clinical trial of EPI-743. SNP-arrays and high-coverage whole exome sequencing were performed on the proband, both parents and three unaffected siblings. Subsequent multi-tissue targeted high-depth mitochondrial sequencing was performed using custom long-range PCR amplicons. Tissue-specific mutant load was also assessed by qPCR. Complex I was interrogated by spectrophotometric enzyme assays and Western Blot. No putatively causal mutations were identified in nuclear-encoded genes. …

Eccentric Muscle Challenge Shows Osteopontin Polymorphism Modulation Of Muscle Damage., Whitney L. Barfield, Kitipong Uaesoontrachoon, Chung-Sheih Wu, Stephen Lin, Yue Chen, Paul C. Wang, Yasmine Kanaan, Vernon Bond, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

A promoter polymorphism of the osteopontin (OPN) gene (rs28357094) has been associated with multiple inflammatory states, severity of Duchenne muscular dystrophy (DMD) and muscle size in healthy young adults. We sought to define the mechanism of action of the polymorphism, using allele-specific in vitroreporter assays in muscle cells, and a genotype-stratified intervention in healthy controls. In vitro reporter constructs showed the G allele to respond to estrogen treatment, whereas the T allele showed no transcriptional response. Young adult volunteers (n = 187) were enrolled into a baseline study, and subjects with specific rs28357094 genotypes enrolled into an eccentric …

Increased 5-Hydroxymethylcytosine And Decreased 5-Methylcytosine Are Indicators Of Global Epigenetic Dysregulation In Diffuse Intrinsic Pontine Glioma, Sama Ahsan, Eric H. Raabe, Michael C. Haffner, Ajay Vaghasia, Katherine E. Warren, Martha Quezado, Leomar Y. Ballester, Javad Nazarian, Charles G. Eberhart, Fausto J. Rodriguez

Genomics and Precision Medicine Faculty Publications

Introduction

Diffuse intrinsic pontine glioma (DIPG) is a malignant pediatric brain tumor associated with dismal outcome. Recent high-throughput molecular studies have shown a high frequency of mutations in histone-encoding genes (H3F3A and HIST1B) and distinctive epigenetic alterations in these tumors. Epigenetic alterations described in DIPG include global DNA hypomethylation. In addition to the generally repressive methylcytosine DNA alteration, 5-hydroxymethylation of cytosine (5hmC) is recognized as an epigenetic mark associated with active chromatin. We hypothesized that in addition to alterations in DNA methylation, that there would be changes in 5hmC. To test this hypothesis, we performed immunohistochemical studies to …

High Hiv Incidence In The Postpartum Period Sustains Vertical Transmission In Settings With Generalized Epidemics: A Cohort Study In Southern Mozambique, Caroline De Schacht, Nedia Mabunda, Orlando C. Ferreira Jr., Nalia Ismael, Nurbai Calu, Iolanda Santos, Heather J. Hoffman, Catharina Alons, Laura Guay, Ilesh V. Jani

Genomics and Precision Medicine Faculty Publications

Introduction: Acute infection with HIV in the postpartum period results in a high risk of vertical transmission through breastfeeding. A study was done to determine the HIV incidence rate and associated risk factors among postpartum women in Southern Mozambique, where HIV prevalence among pregnant women is 21%.

Methods: A prospective cohort study was conducted in six rural health facilities in Gaza and Maputo provinces from March 2008 to July 2011. A total of 1221 women who were HIV-negative on testing at delivery or within two months postpartum were recruited and followed until 18 months postpartum. HIV testing, collection …

Expression Pattern And Biochemical Properties Of Zebrafish N-Acetylglutamate Synthase, Ljubica Caldovic, Nantaporn Haskins, Amy Mumo, Himani Majumdar, Mary Pinter, Mendel Tuchman, Alison Krufka

Genomics and Precision Medicine Faculty Publications

The urea cycle converts ammonia, a waste product of protein catabolism, into urea. Because fish dispose ammonia directly into water, the role of the urea cycle in fish remains unknown. Six enzymes, N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase III, ornithine transcarbamylase, argininosuccinate synthase, argininosuccinate lyase and arginase 1, and two membrane transporters, ornithine transporter and aralar, comprise the urea cycle. The genes for all six enzymes and both transporters are present in the zebrafish genome. NAGS (EC 2.3.1.1) catalyzes the formation of N-acetylglutamate from glutamate and acetyl coenzyme A and in zebrafish is partially inhibited by L-arginine. NAGS and other urea …

Dysferlin Regulates Cell Membrane Repair By Facilitating Injury-Triggered Acid Sphingomyelinase Secretion, Aurelia Defour, Jack H. Van Der Meulen, Rujuta R. Bhatt, Anne Bigot, R. Bashir, Kanneboyina Nagaraju, Jyoti K. Jaiswal

Genomics and Precision Medicine Faculty Publications

Dysferlin deficiency compromises the repair of injured muscle, but the underlying cellular mechanism remains elusive. To study this phenomenon, we have developed mouse and human myoblast models for dysferlinopathy. These dysferlinopathic myoblasts undergo normal differentiation but have a deficit in their ability to repair focal injury to their cell membrane. Imaging cells undergoing repair showed that dysferlin-deficit decreased the number of lysosomes present at the cell membrane, resulting in a delay and reduction in injury-triggered lysosomal exocytosis. We find repair of injured cells does not involve formation of intracellular membrane patch through lysosome–lysosome fusion; instead, individual lysosomes fuse with the …

Knowledge-Fused Differential Dependency Network Models For Detecting Significant Rewiring In Biological Networks, Ye Tian, Bai Zhang, Eric P. Hoffman, Robert Clarke, Zhen Zhang, Ie-Ming Shih, Jianhua Xuan, David M. Herrington, Yue Wang

Genomics and Precision Medicine Faculty Publications

Background

Modeling biological networks serves as both a major goal and an effective tool of systems biology in studying mechanisms that orchestrate the activities of gene products in cells. Biological networks are context-specific and dynamic in nature. To systematically characterize the selectively activated regulatory components and mechanisms, modeling tools must be able to effectively distinguish significant rewiring from random background fluctuations. While differential networks cannot be constructed by existing knowledge alone, novel incorporation of prior knowledge into data-driven approaches can improve the robustness and biological relevance of network inference. However, the major unresolved roadblocks include: big solution space but a …

Non-Invasive Mri And Spectroscopy Of Mdx Mice Reveal Temporal Changes In Dystrophic Muscle Imaging And In Energy Deficits., Christopher R. Heier, Alfredo D. Guerron, Alexandru Korotcov, Stephen Lin, Heather Gordish-Dressman, Stanley Fricke, Raymond W. Sze, Eric P. Hoffman, Paul Wang, Kanneboyina Nagaraju

Genomics and Precision Medicine Faculty Publications

In Duchenne muscular dystrophy (DMD), a genetic disruption of dystrophin protein expression results in repeated muscle injury and chronic inflammation. Magnetic resonance imaging shows promise as a surrogate outcome measure in both DMD and rehabilitation medicine that is capable of predicting clinical benefit years in advance of functional outcome measures. The mdx mouse reproduces the dystrophin deficiency that causes DMD and is routinely used for preclinical drug testing. There is a need to develop sensitive, non-invasive outcome measures in the mdx model that can be readily translatable to human clinical trials. Here we report the use of magnetic resonance imaging …

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 …