Medicine and Health Sciences Commons^™

A Human Endothelial Cell-Based Recycling Assay For Screening Of Fcrn Targeted Molecules., Algirdas Grevys, Jeannette Nilsen, Kine M K Sand, Muluneh B Daba, Inger Øynebråten, Malin Bern, Martin B Mcadam, Stian Foss, Tilman Schlothauer, Terje E Michaelsen, Gregory J. Christianson, Derry C. Roopenian, Richard S Blumberg, Inger Sandlie, Jan Terje Andersen

Faculty Research 2018

Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, …

Triple Vectors Expand Aav Transfer Capacity In The Retina., Andrea Maddalena, Patrizia Tornabene, Paola Tiberi, Renato Minopoli, Anna Manfredi, Margherita Mutarelli, Settimio Rossi, Francesca Simonelli, Juergen K. Naggert, Davide Cacchiarelli, Alberto Auricchio

Faculty Research 2018

Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alström syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected …

The Role Of Ceramide Synthases In The Pathogenicity Of Cryptococcus Neoformans., Mansa A Munshi, Justin M Gardin, Ashutosh Singh, Chiara Luberto, Robert Rieger, Tejas Bouklas, Bettina C Fries, Maurizio Del Poeta

Faculty Research 2018

Cryptococcus neoformans (C. neoformans) is estimated to cause about 220,000 new cases every year in patients with AIDS, despite advances in antifungal treatments. C. neoformans possesses a remarkable ability to disseminate through an immunocompromised host, making treatment difficult. Here, we examine the mechanism of survival of C. neoformans under varying host conditions and find a role for ceramide synthase in C. neoformans virulence. This study also provides a detailed lipidomics resource for the fungal lipid research community in addition to discovering a potential target for antifungal therapy. Cell Rep 2018 Feb 6; 22(6):1392-1400

Frataxin-Deficient Neurons And Mice Models Of Friedreich Ataxia Are Improved By Tat-Mtscs-Fxn Treatment., Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros

Faculty Research 2018

Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans-activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT-MTScs-FXN fusion protein to decrease neurodegeneration markers on frataxin-depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues. In mice models of the disease, …

Concussion, Microvascular Injury, And Early Tauopathy In Young Athletes After Impact Head Injury And An Impact Concussion Mouse Model., Chad A Tagge, Andrew M Fisher, Olga V Minaeva, Amanda Gaudreau-Balderrama, Juliet A Moncaster, Xiao-Lei Zhang, Mark W Wojnarowicz, Noel Casey, Haiyan Lu, Olga N Kokiko-Cochran, Sudad Saman, Maria Ericsson, Kristen D. Onos, Ronel Veksler, Vladimir V Senatorov, Asami Kondo, Xiao Z Zhou, Omid Miry, Linnea R Vose, Katisha R Gopaul, Chirag Upreti, Christopher J Nowinski, Robert C Cantu, Victor E Alvarez, Audrey M Hildebrandt, Erich S Franz, Janusz Konrad, James A Hamilton, Ning Hua, Yorghos Tripodis, Andrew T Anderson, Gareth R Howell, Daniela Kaufer, Garth F Hall, Kun P Lu, Richard M Ransohoff, Robin O Cleveland, Neil W Kowall, Thor D Stein, Bruce T Lamb, Bertrand R Huber, William C Moss, Alon Friedman, Patric K Stanton, Ann C Mckee, Lee E Goldstein

Faculty Research 2018

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor …

Improving Interpretation Of Cardiac Phenotypes And Enhancing Discovery With Expanded Knowledge In The Gene Ontology., Ruth C Lovering, Paola Roncaglia, Douglas G Howe, Stanley J F Laulederkind, Varsha K Khodiyar, Tanya Z Berardini, Susan Tweedie, Rebecca E Foulger, David Osumi-Sutherland, Nancy H Campbell, Rachael P Huntley, Philippa J Talmud, Judith A. Blake, Ross Breckenridge, Paul R Riley, Pier D Lambiase, Perry M Elliott, Lucie Clapp, Andrew Tinker, David P. Hill

Faculty Research 2018

BACKGROUND: A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products.

METHODS AND RESULTS: In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene …

The Evolutionary Pattern Of Mutations In Glioblastoma Reveals Therapy-Mediated Selection., Andrea M Muscat, Nicholas C Wong, Katharine J Drummond, Elizabeth M Algar, Mustafa Khasraw, Roel G W Verhaak, Kathryn Field, Mark A Rosenthal, David M Ashley

Faculty Research 2018

Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors …

Mutations In Dna Repair Genes Are Associated With Increased Neo-Antigen Load And Activated T Cell Infiltration In Lung Adenocarcinoma., Young Kwang Chae, Jonathan F Anker, Preeti Bais, Sandeep Namburi, Francis J Giles, Jeffrey H Chuang

Faculty Research 2018

Mutations in DNA repair genes lead to increased genomic instability and mutation frequency. These mutations represent potential biomarkers for cancer immunotherapy efficacy, as high tumor mutational burden has been associated with increased neo-antigens and tumor infiltrating lymphocytes. While mismatch repair mutations have successfully predicted response to anti-PD-1 therapy in colorectal and other cancers, they have not yet been tested for lung cancer, and few have investigated genes from other DNA repair pathways. We utilized TCGA samples to comprehensively immunophenotype lung tumors and analyze the links between DNA repair mutations, neo-antigen and total mutational burden, and tumor immune infiltration. Overall, 73% …

Mechanistic Differences In Neuropathic Pain Modalities Revealed By Correlating Behavior With Global Expression Profiling., Enrique J Cobos, Chelsea A Nickerson, Fuying Gao, Vijayendran Chandran, Inmaculada Bravo-Caparrós, Rafael González-Cano, Priscilla Riva, Nick A Andrews, Alban Latremoliere, Corey R Seehus, Gloria Perazzoli, Francisco R Nieto, Nicole Joller, Michio W Painter, Chi Him Eddie Ma, Takao Omura, Elissa J Chesler, Daniel H Geschwind, Giovanni Coppola, Manu Rangachari, Clifford J Woolf, Michael Costigan

Faculty Research 2018

Chronic neuropathic pain is a major morbidity of neural injury, yet its mechanisms are incompletely understood. Hypersensitivity to previously non-noxious stimuli (allodynia) is a common symptom. Here, we demonstrate that the onset of cold hypersensitivity precedes tactile allodynia in a model of partial nerve injury, and this temporal divergence was associated with major differences in global gene expression in innervating dorsal root ganglia. Transcripts whose expression change correlates with the onset of cold allodynia were nociceptor related, whereas those correlating with tactile hypersensitivity were immune cell centric. Ablation of TrpV1 lineage nociceptors resulted in mice that did not acquire cold …

Transcriptional Regulatory Control Of Mammalian Nephron Progenitors Revealed By Multi-Factor Cistromic Analysis And Genetic Studies., Lori L O'Brien, Qiuyu Guo, Emad Bahrami-Samani, Joo-Seop Park, Sean M Hasso, Young-Jin Lee, Alan Fang, Albert D Kim, Jinjin Guo, Trudy M Hong, Kevin A Peterson, Scott Lozanoff, Ramya Raviram, Bing Ren, Ben Fogelgren, Andrew D Smith, Anton Valouev, Andrew P Mcmahon

Faculty Research 2018

Nephron progenitor number determines nephron endowment; a reduced nephron count is linked to the onset of kidney disease. Several transcriptional regulators including Six2, Wt1, Osr1, Sall1, Eya1, Pax2, and Hox11 paralogues are required for specification and/or maintenance of nephron progenitors. However, little is known about the regulatory intersection of these players. Here, we have mapped nephron progenitor-specific transcriptional networks of Six2, Hoxd11, Osr1, and Wt1. We identified 373 multi-factor associated 'regulatory hotspots' around genes closely associated with progenitor programs. To examine their functional significance, we deleted 'hotspot' enhancer elements for Six2 and Wnt4. Removal of the distal enhancer for Six2 …

Developmental Constraint Through Negative Pleiotropy In The Zygomatic Arch., Christopher J Percival, Rebecca Green, Charles C Roseman, Daniel M. Gatti, Judy Morgan, Stephen A. Murray, Leah Rae Donahue, Jessica M Mayeux, K Michael Pollard, Kunjie Hua, Daniel Pomp, Ralph Marcucio, Benedikt Hallgrímsson

Faculty Research 2018

Background: Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains. If the negative correlation of adjacent bone lengths is associated with genetic variation in a heterogeneous population, it would be an example of negative pleiotropy, which occurs when a genetic factor leads to opposite effects in two phenotypes. Confirming negative pleiotropy and determining its basis may reveal important information about the maintenance of overall skull integration and developmental constraint on skull morphology.

Results: We identified negative correlations between the lengths of the frontal and parietal bones in the midline cranial …

Gearing Up To Handle The Mosaic Nature Of Life In The Quest For Orthologs., Kristoffer Forslund, Cecile Pereira, Salvador Capella-Gutierrez, Alan Sousa Da Silva, Adrian Altenhoff, Jaime Huerta-Cepas, Matthieu Muffato, Mateus Patricio, Klaas Vandepoele, Ingo Ebersberger, Judith A. Blake, Jesualdo Tomás Fernández Breis, The Quest For Orthologs Consortium, Brigitte Boeckmann, Toni Gabaldón, Erik Sonnhammer, Christophe Dessimoz, Suzanna Lewis

Faculty Research 2018

The Quest for Orthologs (QfO) is an open collaboration framework for experts in comparative phylogenomics and related research areas who have an interest in highly accurate orthology predictions and their applications. We here report highlights and discussion points from the QfO meeting 2015 held in Barcelona. Achievements in recent years have established a basis to support developments for improved orthology prediction and to explore new approaches. Central to the QfO effort is proper benchmarking of methods and services, as well as design of standardized datasets and standardized formats to allow sharing and comparison of results. Simultaneously, analysis pipelines have been …

Mouse Phenome Database: An Integrative Database And Analysis Suite For Curated Empirical Phenotype Data From Laboratory Mice., Molly A. Bogue, Stephen C. Grubb, David O Walton, Vivek M. Philip, Georgi Kolishovski, Timothy M Stearns, Matthew H Dunn, Daniel A Skelly, Beena Kadakkuzha, Gregg Tehennepe, Govindarajan Kunde-Ramamoorthy, Elissa J Chesler

Faculty Research 2018

The Mouse Phenome Database (MPD; https://phenome.jax.org) is a widely used resource that provides access to primary experimental trait data, genotypic variation, protocols and analysis tools for mouse genetic studies. Data are contributed by investigators worldwide and represent a broad scope of phenotyping endpoints and disease-related traits in naïve mice and those exposed to drugs, environmental agents or other treatments. MPD houses individual animal data with detailed, searchable protocols, and makes these data available to other resources via API. MPD provides rigorous curation of experimental data and supporting documentation using relevant ontologies and controlled vocabularies. Most data in MPD are from …

Tumorfusions: An Integrative Resource For Cancer-Associated Transcript Fusions., Xin Hu, Qianghu Wang, Ming Tang, Floris P Barthel, Samirkumar B Amin, Kosuke Yoshihara, Frederick M Lang, Emmanuel Martinez-Ledesma, Soo Hyun Lee, Siyuan Zheng, Roel G W Verhaak

Faculty Research 2018

Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as …

Consensus Coding Sequence (Ccds) Database: A Standardized Set Of Human And Mouse Protein-Coding Regions Supported By Expert Curation., Shashikant Pujar, Nuala A O'Leary, Catherine M Farrell, Jane E Loveland, Jonathan M Mudge, Craig Wallin, Carlos G Girón, Mark Diekhans, If Barnes, Ruth Bennett, Andrew E Berry, Eric Cox, Claire Davidson, Tamara Goldfarb, Jose M Gonzalez, Toby Hunt, John Jackson, Vinita Joardar, Mike P Kay, Vamsi K Kodali, Fergal J Martin, Monica Mcandrews, Kelly M Mcgarvey, Michael Murphy, Bhanu Rajput, Sanjida H Rangwala, Lillian D Riddick, Ruth L Seal, Marie-Marthe Suner, David Webb, Sophia Zhu, Bronwen L Aken, Elspeth A Bruford, Carol J Bult, Adam Frankish, Terence Murphy, Kim D Pruitt

Faculty Research 2018

The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration …

Jepegmix2: Improved Gene-Level Joint Analysis Of Eqtls In Cosmopolitan Cohorts., Chris Chatzinakos, Donghyung Lee, Bradley T Webb, Vladimir I Vladimirov, Kenneth S Kendler, Silviu-Alin Bacanu

Faculty Research 2018

Motivation: To increase detection power, researchers use gene level analysis methods to aggregate weak marker signals. Due to gene expression controlling biological processes, researchers proposed aggregating signals for expression Quantitative Trait Loci (eQTL). Most gene-level eQTL methods make statistical inferences based on i) summary statistics from genome-wide association studies (GWAS) and ii) linkage disequilibrium (LD) patterns from a relevant reference panel. While most such tools assume homogeneous cohorts, our Gene-level Joint Analysis of functional SNPs in Cosmopolitan Cohorts (JEPEGMIX) method accommodates cosmopolitan cohorts by using heterogeneous panels. However, JEPGMIX relies on brain eQTLs from older gene expression studies and does …

Nicotinamide Treatment Robustly Protects From Inherited Mouse Glaucoma., Pete A. Williams, Jeffrey M. Harder, Brynn H Cardozo, Nicole E Foxworth, Simon W M John

Faculty Research 2018

Nicotinamide adenine dinucleotide (NAD) is a key molecule in several cellular processes and is essential for healthy mitochondrial metabolism. We recently reported that mitochondrial dysfunction is among the very first changes to occur within retinal ganglion cells during initiation of glaucoma in DBA/2J mice. Furthermore, we demonstrated that an age-dependent decline of NAD contributes to mitochondrial dysfunction and vulnerability to glaucoma. The decrease in NAD renders retinal ganglion cells vulnerable to a metabolic crisis following periods of high intraocular pressure. Treating mice with the NAD precursor nicotinamide (the amide form of vitamin B₃) inhibited many age- and high …

Adam17 Is Essential For Ectodomain Shedding Of The Egf-Receptor Ligand Amphiregulin., Vishnu Hosur, Michelle L Farley, Lisa M. Burzenski, Leonard D. Shultz, Michael V. Wiles

Faculty Research 2018

The epidermal growth factor (EGF)-receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG, synthesized as a propeptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although (ADAM17) a disintegrin and metalloprotease 17 is a key sheddase of AREG, ADAM8-, ADAM15-, and batimastat (broad metalloprotease inhibitor)-sensitive metalloproteases have also been implicated in AREG shedding. In the present study, using a curly bare (Rhbdf2^cub ) mouse model that shows loss-of-hair, enlarged sebaceous gland, and rapid cutaneous wound-healing phenotypes mediated by …

Modularity Of The Metabolic Gene Network As A Prognostic Biomarker For Hepatocellular Carcinoma., Fengdan Ye, Dongya Jia, Mingyang Lu, Herbert Levine, Michael W Deem

Faculty Research 2018

Abnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later …

Sensing The Cilium, Digital Capture Of Ciliary Data For Comparative Genomics Investigations., Karen R. Christie, Judith A. Blake

Faculty Research 2018

Cilia are specialized, hair-like structures that project from the cell bodies of eukaryotic cells. With increased understanding of the distribution and functions of various types of cilia, interest in these organelles is accelerating. To effectively use this great expansion in knowledge, this information must be made digitally accessible and available for large-scale analytical and computational investigation. Capture and integration of knowledge about cilia into existing knowledge bases, thus providing the ability to improve comparative genomic data analysis, is the objective of this work. Cilia 2018; 7:3.

Exploring Autophagy With Gene Ontology., Paul Denny, Marc Feuermann, David P. Hill, Ruth C Lovering, Helene Plun-Favreau, Paola Roncaglia

Faculty Research 2018

Autophagy is a fundamental cellular process that is well conserved among eukaryotes. It is one of the strategies that cells use to catabolize substances in a controlled way. Autophagy is used for recycling cellular components, responding to cellular stresses and ridding cells of foreign material. Perturbations in autophagy have been implicated in a number of pathological conditions such as neurodegeneration, cardiac disease and cancer. The growing knowledge about autophagic mechanisms needs to be collected in a computable and shareable format to allow its use in data representation and interpretation. The Gene Ontology (GO) is a freely available resource that describes …

The International Mouse Phenotyping Consortium (Impc): A Functional Catalogue Of The Mammalian Genome That Informs Conservation., Violeta Muñoz-Fuentes, Pilar Cacheiro, Terrence F Meehan, Juan Antonio Aguilar-Pimentel, Steve D M Brown, Ann M Flenniken, Paul Flicek, Antonella Galli, Hamed Haseli Mashhadi, Martin Hrabě De Angelis, Jong Kyoung Kim, K C Kent Lloyd, Colin Mckerlie, Hugh Morgan, Stephen A. Murray, Lauryl M J Nutter, Patrick T Reilly, John R Seavitt, Je Kyung Seong, Michelle Simon, Hannah Wardle-Jones, Ann-Marie Mallon, Damian Smedley, Helen E Parkinson

Faculty Research 2018

The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development …

Genomic Profiling Of T-Cell Neoplasms Reveals Frequent, Allison Greenplate, Kai Wang, Rati M Tripathi, Norma Palma, Siraj M Ali, Phil J Stephens, Vincent A Miller, Yu Shyr, Yan Guo, Nishitha M Reddy, Lina Kozhaya, Derya Unutmaz, Xueyan Chen, Jonathan M Irish, Utpal P Davé

Faculty Research 2018

Purpose: The promise of precision oncology is that identification of genomic alterations will direct the rational use of molecularly targeted therapy. This approach is particularly applicable to neoplasms that are resistant to standard cytotoxic chemotherapy, like T-cell leukemias and lymphomas. In this study, we tested the feasibility of targeted next-generation sequencing in profiles of diverse T-cell neoplasms and focused on the therapeutic utility of targeting activated JAK1 and JAK3 in an index case.

Patients and Methods: Using Foundation One and Foundation One Heme assays, we performed genomic profiling on 91 consecutive T-cell neoplasms for alterations in 405 genes. The samples …

Determination Of T Follicular Helper Cell Fate By Dendritic Cells., Jayendra Kumar Krishnaswamy, Samuel Alsén, Ulf Yrlid, Stephanie C Eisenbarth, Adam Williams

Faculty Research 2018

T follicular helper (Tfh) cells are a specialized subset of CD4⁺ T cells that collaborate with B cells to promote and regulate humoral responses. Unlike other CD4⁺ effector lineages, Tfh cells require interactions with both dendritic cells (DCs) and B cells to complete their differentiation. While numerous studies have assessed the potential of different DC subsets to support Tfh priming, the conclusions of these studies depend heavily on the model and method of immunization used. We propose that the location of different DC subsets within the lymph node (LN) and their access to antigen determine their potency in …

Synthetic Peptide Ck2.3 Enhances Bone Mineral Density In Senile Mice., John Nguyen, Hilary Weidner, Lora M Schell, Linda Sequeira, Ryan Kabrick, Saurabh Dharmadhikari, Harold Coombs, Randall L Duncan, Liyun Wang, Anja Nohe

Faculty Research 2018

Background: Osteoporosis is a silent disease caused by low bone mineral density that results in bone fractures in 1 out of 2 women and 1 in 4 men over the age of 50. Although several treatments for osteopenia and osteoporosis are available, they have severe side effects and new treatments are desperately needed. Current treatments usually target osteoclasts and inhibit their activity or differentiation. Treatments that decrease osteoclast differentiation and activity but enhance osteogenesis and osteoblast activity are not available. We recently developed a peptide, CK2.3, that induces bone formation and increases bone mineral density as demonstrated by injection over …

"Of Mice And Measures": A Project To Improve How We Advance Duchenne Muscular Dystrophy Therapies To The Clinic., Heather Gordish-Dressman, Raffaella Willmann, Laura Dalle Pazze, Arati Kreibich, Maaike Van Putten, Ahlke Heydemann, Laurent P. Bogdanik, Cathleen Lutz, Kay Davies, Alexis R Demonbruen, Dongsheng Duan, David Elsey, So-Ichiro Fukada, Mahasweta Girgenrath, J Patrick Gonzalez, Miranda D Grounds, Andy Nichols, Terry Partridge, Marco Passini, Francesca Sanarica, Frederick J Schnell, Dominic J Wells, Toshifumi Yokota, Courtney S Young, Zhong Zhong, Christopher Spurney, Melissa Spencer, Annamaria De Luca, Kanneboyina Nagaraju, Annemieke Aartsma-Rus

Faculty Research 2018

A new line of dystrophic mdx mice on the DBA/2J (D2) background has emerged as a candidate to study the efficacy of therapeutic approaches for Duchenne muscular dystrophy (DMD). These mice harbor genetic polymorphisms that appear to increase the severity of the dystropathology, with disease modifiers that also occur in DMD patients, making them attractive for efficacy studies and drug development. This workshop aimed at collecting and consolidating available data on the pathological features and the natural history of these new D2/mdx mice, for comparison with classic mdx mice and controls, and to identify gaps in information and their potential …

Sebaceous Gland Abnormalities In Fatty Acyl Coa Reductase 2 (Far2) Null Mice Result In Primary Cicatricial Alopecia., John P Sundberg, Tong Shen, Oliver Fiehn, Robert H Rice, Kathleen A Silva, Victoria E. Kennedy, Nicholas E Gott, Louise A. Dionne, Lesley S Bechtold, Stephen A. Murray, Raoul Kuiper, C Herbert Pratt

Faculty Research 2018

In a large scale screen for skin, hair, and nail abnormalities in null mice generated by The Jackson Laboratory's KOMP center, homozygous mutant Far2tm2b(KOMP)Wtsi/2J (hereafter referrred to as Far2-/-) mice were found to develop focal areas of alopecia as they aged. As sebocytes matured in wildtype C57BL/NJ mice they became pale with fine, uniformly sized clear lipid containing vacuoles that were released when sebocytes disintegrated in the duct. By contrast, the Far2-/- null mice had sebocytes that were similar within the gland but become brightly eosinophilic when the cells entered the sebaceous gland duct. As sebocytes disintegrated, their contents did …

Editorial: Axonopathy In Neurodegenerative Disease., Robert W. Burgess, Samuel D Crish

Faculty Research 2018

No abstract provided.