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2019

The Jackson Laboratory

JMG

Articles 1 - 30 of 67

Full-Text Articles in Life Sciences

Growth Differentiation Factor 11 Locally Controls Anterior-Posterior Patterning Of The Axial Skeleton., Joonho Suh, Je-Hyun Eom, Na-Kyung Kim, Kyung Mi Woo, Jeong-Hwa Baek, Hyun-Mo Ryoo, Se-Jin Lee, Yun-Sil Lee Dec 2019

Growth Differentiation Factor 11 Locally Controls Anterior-Posterior Patterning Of The Axial Skeleton., Joonho Suh, Je-Hyun Eom, Na-Kyung Kim, Kyung Mi Woo, Jeong-Hwa Baek, Hyun-Mo Ryoo, Se-Jin Lee, Yun-Sil Lee

Faculty Research 2019

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β family member that has been identified as the central player of anterior-posterior (A-P) axial skeletal patterning. Mice homozygous for Gdf11 deletion exhibit severe anterior homeotic transformations of the vertebrae and craniofacial defects. During early embryogenesis, Gdf11 is expressed predominantly in the primitive streak and tail bud regions, where new mesodermal cells arise. On the basis of this expression pattern of Gdf11 and the phenotype of Gdf11 mutant mice, it has been suggested that GDF11 acts to specify positional identity along the A-P axis either by local changes in ...


Increased Interactions And Engulfment Of Dendrites By Microglia Precede Purkinje Cell Degeneration In A Mouse Model Of Niemann Pick Type-C., Larisa Kavetsky, Kayla K Green, Bridget R Boyle, Fawad A K Yousufzai, Zachary M Padron, Sierra E Melli, Victoria L Kuhnel, Harriet M. Jackson, Rosa E Blanco, Gareth R Howell, Ileana Soto Oct 2019

Increased Interactions And Engulfment Of Dendrites By Microglia Precede Purkinje Cell Degeneration In A Mouse Model Of Niemann Pick Type-C., Larisa Kavetsky, Kayla K Green, Bridget R Boyle, Fawad A K Yousufzai, Zachary M Padron, Sierra E Melli, Victoria L Kuhnel, Harriet M. Jackson, Rosa E Blanco, Gareth R Howell, Ileana Soto

Faculty Research 2019

Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1nmf164 mouse cerebellum, microglia ...


Early-Life Dna Methylation Profiles Are Indicative Of Age-Related Transcriptome Changes., Niran Hadad, Dustin R Masser, Laura Blanco-Berdugo, David R Stanford, Willard M Freeman Oct 2019

Early-Life Dna Methylation Profiles Are Indicative Of Age-Related Transcriptome Changes., Niran Hadad, Dustin R Masser, Laura Blanco-Berdugo, David R Stanford, Willard M Freeman

Faculty Research 2019

BACKGROUND: Alterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood.

RESULTS: Paired analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers. Altered promoter methylation with aging was found to be generally un-related to ...


A Mutation In Mouse Krüppel-Like Factor 15 Alters The Gut Microbiome And Response To Obesogenic Diet., Karen L. Svenson, Lauren L Long, Steven L. Ciciotte, Mark D Adams Sep 2019

A Mutation In Mouse Krüppel-Like Factor 15 Alters The Gut Microbiome And Response To Obesogenic Diet., Karen L. Svenson, Lauren L Long, Steven L. Ciciotte, Mark D Adams

Faculty Research 2019

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high ...


C57bl/6 Substrain Differences In Pharmacological Effects After Acute And Repeated Nicotine Administration., Lois S Akinola, Bryan Mckiver, Wisam Toma, Andy Z X Zhu, Rachel F Tyndale, Vivek Kumar, M Imad Damaj Sep 2019

C57bl/6 Substrain Differences In Pharmacological Effects After Acute And Repeated Nicotine Administration., Lois S Akinola, Bryan Mckiver, Wisam Toma, Andy Z X Zhu, Rachel F Tyndale, Vivek Kumar, M Imad Damaj

Faculty Research 2019

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence. Using the closely related C57BL/6 (B6) mice substrains, recent reports have noted phenotypic differences within C57BL/6J (B6J) and C57BL/6N (B6N) mice for some drugs of abuse: alcohol, opiates, and cocaine. However, the differences in nicotine's effects have not yet ...


Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice., Bradford A Youngblood, Emily C Brock, John Leung, Rustom Falahati, Paul J Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L Greiner, Michael A Brehm, Christopher Bebbington, Nenad Tomasevic Sep 2019

Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice., Bradford A Youngblood, Emily C Brock, John Leung, Rustom Falahati, Paul J Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L Greiner, Michael A Brehm, Christopher Bebbington, Nenad Tomasevic

Faculty Research 2019

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and ...


Visual Discrimination, Serial Reversal, And Extinction Learning In The, Price E. Dickson, Guy Mittleman Aug 2019

Visual Discrimination, Serial Reversal, And Extinction Learning In The, Price E. Dickson, Guy Mittleman

Faculty Research 2019

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and the most common neuromuscular disorder. In addition to neuromuscular consequences, some individuals with DMD experience global intellectual dysfunction and executive dysfunction of unknown mechanistic origin. The cognitive profile of the mdx mouse, the most commonly used mouse model of DMD, has been incompletely characterized and has never been assessed using the touchscreen operant conditioning paradigm. The touchscreen paradigm allows the use of protocols that are virtually identical to those used in human cognitive testing and may, therefore, provide the most translational paradigm for quantifying mouse cognitive function ...


Genetic Determinants Of Gut Microbiota Composition And Bile Acid Profiles In Mice., Julia H Kemis, Vanessa Linke, Kelsey L Barrett, Frederick J Boehm, Lindsay L Traeger, Mark P Keller, Mary E Rabaglia, Kathryn L Schueler, Donald S Stapleton, Daniel M Gatti, Gary A Churchill, Daniel Amador-Noguez, Jason D Russell, Brian S Yandell, Karl W Broman, Joshua J Coon, Alan D Attie, Federico E Rey Aug 2019

Genetic Determinants Of Gut Microbiota Composition And Bile Acid Profiles In Mice., Julia H Kemis, Vanessa Linke, Kelsey L Barrett, Frederick J Boehm, Lindsay L Traeger, Mark P Keller, Mary E Rabaglia, Kathryn L Schueler, Donald S Stapleton, Daniel M Gatti, Gary A Churchill, Daniel Amador-Noguez, Jason D Russell, Brian S Yandell, Karl W Broman, Joshua J Coon, Alan D Attie, Federico E Rey

Faculty Research 2019

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct ...


Spontaneous Mutations Of The Zpld1 Gene In Mice Cause Semicircular Canal Dysfunction But Do Not Impair Gravity Receptor Or Hearing Functions., Sarath Vijayakumar, Sherri M Jones, Timothy A Jones, Cong Tian, Kenneth R. Johnson Aug 2019

Spontaneous Mutations Of The Zpld1 Gene In Mice Cause Semicircular Canal Dysfunction But Do Not Impair Gravity Receptor Or Hearing Functions., Sarath Vijayakumar, Sherri M Jones, Timothy A Jones, Cong Tian, Kenneth R. Johnson

Faculty Research 2019

The cupula is a gelatinous membrane overlying the crista ampullaris of the semicircular canal, important for sensing rotation of the head and critical for normal balance. Recently the zona pellucida like domain containing 1 protein (ZPLD1, also known as cupulin) was identified in the cupula of fish. Here, we describe two new spontaneous mutations in the mouse Zpld1 gene, which were discovered by the circling behavior of mutant mice, an indicator of balance dysfunction. The Zpld1 mutant mice exhibited normal hearing function as assessed by auditory brainstem response (ABR) measurements, and their otolithic organs appeared normal. In the inner ear ...


A First Genetic Portrait Of Synaptonemal Complex Variation., Richard J Wang, Beth L Dumont, Peicheng Jing, Bret A Payseur Aug 2019

A First Genetic Portrait Of Synaptonemal Complex Variation., Richard J Wang, Beth L Dumont, Peicheng Jing, Bret A Payseur

Faculty Research 2019

The synaptonemal complex (SC) is a proteinaceous scaffold required for synapsis and recombination between homologous chromosomes during meiosis. Although the SC has been linked to differences in genome-wide crossover rates, the genetic basis of standing variation in SC structure remains unknown. To investigate the possibility that recombination evolves through changes to the SC, we characterized the genetic architecture of SC divergence on two evolutionary timescales. Applying a novel digital image analysis technique to spermatocyte spreads, we measured total SC length in 9,532 spermatocytes from recombinant offspring of wild-derived mouse strains with differences in this fundamental meiotic trait. Using this ...


Hepsin-Mediated Processing Of Uromodulin Is Crucial For Salt-Sensitivity And Thick Ascending Limb Homeostasis., Eric Olinger, Jennifer Lake, Susan Sheehan, Guglielmo Schiano, Tomoaki Takata, Natsuko Tokonami, Huguette Debaix, Francesco Consolato, Luca Rampoldi, Ron Korstanje, Olivier Devuyst Aug 2019

Hepsin-Mediated Processing Of Uromodulin Is Crucial For Salt-Sensitivity And Thick Ascending Limb Homeostasis., Eric Olinger, Jennifer Lake, Susan Sheehan, Guglielmo Schiano, Tomoaki Takata, Natsuko Tokonami, Huguette Debaix, Francesco Consolato, Luca Rampoldi, Ron Korstanje, Olivier Devuyst

Faculty Research 2019

Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of ...


Transcriptome Profiling Of Brain Myeloid Cells Revealed Activation Of Itgal, Trem1, And Spp1 In Western Diet-Induced Obesity., Hongtian Yang, Leah C. Graham, Alaina M Reagan, Weronika Grabowska, William H. Schott, Gareth R Howell Aug 2019

Transcriptome Profiling Of Brain Myeloid Cells Revealed Activation Of Itgal, Trem1, And Spp1 In Western Diet-Induced Obesity., Hongtian Yang, Leah C. Graham, Alaina M Reagan, Weronika Grabowska, William H. Schott, Gareth R Howell

Faculty Research 2019

BACKGROUND: Environmental factors are critical in the development of age-related cognitive decline and dementia. A western diet (WD) can cause nutrient deficiency and inflammation that could impact cognition directly. It is increasingly recognized that innate immune responses by brain myeloid cells, such as resident microglia, and infiltrating peripheral monocytes/macrophages may represent an essential link between a WD, cognitive decline, and dementia. Our previous data demonstrated that chronic consumption of a WD induced inflammation through brain myeloid cells in aging mice and a mouse model of Alzheimer's disease (AD). However, the subtypes of myeloid cells that contribute to the ...


Doxorubicin-Induced Cardiotoxicity In Collaborative Cross (Cc) Mice Recapitulates Individual Cardiotoxicity In Humans., Caroline J Zeiss, Daniel M Gatti, Olga Toro-Salazar, Crystal Davis, Cathleen M Lutz, Francis Spinale, Timothy M Stearns, Milena B Furtado, Gary A Churchill Aug 2019

Doxorubicin-Induced Cardiotoxicity In Collaborative Cross (Cc) Mice Recapitulates Individual Cardiotoxicity In Humans., Caroline J Zeiss, Daniel M Gatti, Olga Toro-Salazar, Crystal Davis, Cathleen M Lutz, Francis Spinale, Timothy M Stearns, Milena B Furtado, Gary A Churchill

Faculty Research 2019

Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of ...


Meox2 Haploinsufficiency Accelerates Axonal Degeneration In Dba/2j Glaucoma., Rebecca A Buchanan, Kate E Foley, Keating W. Pepper, Alaina M Reagan, Kelly J Keezer, Amanda A Hewes, Cory A Diemler, Christoph Preuss, Ileana Soto, Simon W M John, Gareth R Howell Aug 2019

Meox2 Haploinsufficiency Accelerates Axonal Degeneration In Dba/2j Glaucoma., Rebecca A Buchanan, Kate E Foley, Keating W. Pepper, Alaina M Reagan, Kelly J Keezer, Amanda A Hewes, Cory A Diemler, Christoph Preuss, Ileana Soto, Simon W M John, Gareth R Howell

Faculty Research 2019

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma.

Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a ...


Identifying And Ranking Potential Driver Genes Of Alzheimer's Disease Using Multiview Evidence Aggregation., Sumit Mukherjee, Thanneer M Perumal, Kenneth Daily, Solveig K Sieberts, Larsson Omberg, Christoph Preuss, Gregory W. Carter, Lara M Mangravite, Benjamin A Logsdon Jul 2019

Identifying And Ranking Potential Driver Genes Of Alzheimer's Disease Using Multiview Evidence Aggregation., Sumit Mukherjee, Thanneer M Perumal, Kenneth Daily, Solveig K Sieberts, Larsson Omberg, Christoph Preuss, Gregory W. Carter, Lara M Mangravite, Benjamin A Logsdon

Faculty Research 2019

MOTIVATION: Late onset Alzheimer's disease is currently a disease with no known effective treatment options. To better understand disease, new multi-omic data-sets have recently been generated with the goal of identifying molecular causes of disease. However, most analytic studies using these datasets focus on uni-modal analysis of the data. Here, we propose a data driven approach to integrate multiple data types and analytic outcomes to aggregate evidences to support the hypothesis that a gene is a genetic driver of the disease. The main algorithmic contributions of our article are: (i) a general machine learning framework to learn the key ...


Drug Safety Africa: An Overview Of Safety Pharmacology & Toxicology In South Africa., Brian D Guth, Anne F Grobler, Kendall S Frazier, Andrea Greiter-Wilke, Danuta Herzyk, Tertius A Hough, Asrar Ali Khan, Michael Markert, James D Smith, Karen L. Svenson, Sara Wells, Michael K Pugsley Jul 2019

Drug Safety Africa: An Overview Of Safety Pharmacology & Toxicology In South Africa., Brian D Guth, Anne F Grobler, Kendall S Frazier, Andrea Greiter-Wilke, Danuta Herzyk, Tertius A Hough, Asrar Ali Khan, Michael Markert, James D Smith, Karen L. Svenson, Sara Wells, Michael K Pugsley

Faculty Research 2019

This meeting report is based on presentations given at the first Drug Safety Africa Meeting in Potchefstroom, South Africa from November 20-22, 2018 at the North-West University campus. There were 134 attendees (including 26 speakers and 34 students) from the pharmaceutical industry, academia, regulatory agencies as well as 6 exhibitors. These meeting proceedings are designed to inform the content that was presented in terms of Safety Pharmacology (SP) and Toxicology methods and models that are used by the pharmaceutical industry to characterize the safety profile of novel small chemical or biological molecules. The first part of this report includes an ...


Genomic Data Analysis Workflows For Tumors From Patient-Derived Xenografts (Pdxs): Challenges And Guidelines., Xing Yi Woo, Anuj Srivastava, Joel H Graber, Vinod Yadav, Vishal Kumar Sarsani, Allen K. Simons, Glen L Beane, Stephen C. Grubb, Guruprasad Ananda, Rangjiao Liu, Grace Stafford, Jeffrey Chuang, Susan Airhart, Radha Krishna Murthy Karuturi, Joshy George, Carol J Bult Jul 2019

Genomic Data Analysis Workflows For Tumors From Patient-Derived Xenografts (Pdxs): Challenges And Guidelines., Xing Yi Woo, Anuj Srivastava, Joel H Graber, Vinod Yadav, Vishal Kumar Sarsani, Allen K. Simons, Glen L Beane, Stephen C. Grubb, Guruprasad Ananda, Rangjiao Liu, Grace Stafford, Jeffrey Chuang, Susan Airhart, Radha Krishna Murthy Karuturi, Joshy George, Carol J Bult

Faculty Research 2019

BACKGROUND: Patient-derived xenograft (PDX) models are in vivo models of human cancer that have been used for translational cancer research and therapy selection for individual patients. The Jackson Laboratory (JAX) PDX resource comprises 455 models originating from 34 different primary sites (as of 05/08/2019). The models undergo rigorous quality control and are genomically characterized to identify somatic mutations, copy number alterations, and transcriptional profiles. Bioinformatics workflows for analyzing genomic data obtained from human tumors engrafted in a mouse host (i.e., Patient-Derived Xenografts; PDXs) must address challenges such as discriminating between mouse and human sequence reads and accurately ...


Hsp90 Inhibitor, Nvp-Auy922, Improves Myelination In Vitro And Supports The Maintenance Of Myelinated Axons In Neuropathic Mice., Vinita G Chittoor-Vinod, Hannah Bazick, Adrian G Todd, Darin Falk, Kathryn H Morelli, Robert W. Burgess, Thomas C Foster, Lucia Notterpek Jun 2019

Hsp90 Inhibitor, Nvp-Auy922, Improves Myelination In Vitro And Supports The Maintenance Of Myelinated Axons In Neuropathic Mice., Vinita G Chittoor-Vinod, Hannah Bazick, Adrian G Todd, Darin Falk, Kathryn H Morelli, Robert W. Burgess, Thomas C Foster, Lucia Notterpek

Faculty Research 2019

Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell culture models, we previously validated the chaperone pathway as a viable target for therapy development. Here, we tested five commercially available inhibitors of HSP90 and identified BIIB021 and AUY922 to support Schwann cell viability and enhance chaperone expression. AUY922 showed higher efficacy, compared to BIIB021, in enhancing myelin synthesis in dorsal root ganglion explant cultures from neuropathic mice. For in vivo testing, we randomly assigned 2-3 ...


Probabilistic Modeling Of Personalized Drug Combinations From Integrated Chemical Screen And Molecular Data In Sarcoma., Noah E Berlow, Rishi Rikhi, Mathew Geltzeiler, Jinu Abraham, Matthew N Svalina, Lara E Davis, Erin Wise, Maria Mancini, Jonathan Noujaim, Atiya Mansoor, Michael J Quist, Kevin L Matlock, Martin W Goros, Brian S Hernandez, Yee C Doung, Khin Thway, Tomohide Tsukahara, Jun Nishio, Elaine T Huang, Susan Airhart, Carol J Bult, Regina Gandour-Edwards, Robert G Maki, Robin L Jones, Joel E Michalek, Milan Milovancev, Souparno Ghosh, Ranadip Pal, Charles Keller Jun 2019

Probabilistic Modeling Of Personalized Drug Combinations From Integrated Chemical Screen And Molecular Data In Sarcoma., Noah E Berlow, Rishi Rikhi, Mathew Geltzeiler, Jinu Abraham, Matthew N Svalina, Lara E Davis, Erin Wise, Maria Mancini, Jonathan Noujaim, Atiya Mansoor, Michael J Quist, Kevin L Matlock, Martin W Goros, Brian S Hernandez, Yee C Doung, Khin Thway, Tomohide Tsukahara, Jun Nishio, Elaine T Huang, Susan Airhart, Carol J Bult, Regina Gandour-Edwards, Robert G Maki, Robin L Jones, Joel E Michalek, Milan Milovancev, Souparno Ghosh, Ranadip Pal, Charles Keller

Faculty Research 2019

BACKGROUND: Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments.

METHODS: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach ...


Changes In The Gut Microbiome And Fermentation Products Concurrent With Enhanced Longevity In Acarbose-Treated Mice., Byron J Smith, Richard A Miller, Aaron C Ericsson, David E Harrison, Randy Strong, Thomas M Schmidt Jun 2019

Changes In The Gut Microbiome And Fermentation Products Concurrent With Enhanced Longevity In Acarbose-Treated Mice., Byron J Smith, Richard A Miller, Aaron C Ericsson, David E Harrison, Randy Strong, Thomas M Schmidt

Faculty Research 2019

BACKGROUND: Treatment with the α-glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to ...


A Computational Method To Aid The Design And Analysis Of Single Cell Rna-Seq Experiments For Cell Type Identification., Douglas Abrams, Parveen Kumar, Radha Krishna Murthy Karuturi, Joshy George Jun 2019

A Computational Method To Aid The Design And Analysis Of Single Cell Rna-Seq Experiments For Cell Type Identification., Douglas Abrams, Parveen Kumar, Radha Krishna Murthy Karuturi, Joshy George

Faculty Research 2019

BACKGROUND: The advent of single cell RNA sequencing (scRNA-seq) enabled researchers to study transcriptomic activity within individual cells and identify inherent cell types in the sample. Although numerous computational tools have been developed to analyze single cell transcriptomes, there are no published studies and analytical packages available to guide experimental design and to devise suitable analysis procedure for cell type identification.

RESULTS: We have developed an empirical methodology to address this important gap in single cell experimental design and analysis into an easy-to-use tool called SCEED (Single Cell Empirical Experimental Design and analysis). With SCEED, user can choose a variety ...


Glycine Supplementation Extends Lifespan Of Male And Female Mice., Richard A Miller, David E Harrison, Clinton Michael Astle, Molly A. Bogue, Joel Brind, Elizabeth Fernandez, Kevin Flurkey, Martin Javors, Warren Ladiges, Christiaan Leeuwenburgh, Francesca Macchiarini, James Nelson, Alexey G Ryazanov, Jessica Snyder, Timothy M Stearns, Douglas E Vaughan, Randy Strong Jun 2019

Glycine Supplementation Extends Lifespan Of Male And Female Mice., Richard A Miller, David E Harrison, Clinton Michael Astle, Molly A. Bogue, Joel Brind, Elizabeth Fernandez, Kevin Flurkey, Martin Javors, Warren Ladiges, Christiaan Leeuwenburgh, Francesca Macchiarini, James Nelson, Alexey G Ryazanov, Jessica Snyder, Timothy M Stearns, Douglas E Vaughan, Randy Strong

Faculty Research 2019

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males. End-of-life necropsies suggested that glycine-treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine-supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI-1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.


Effects Of Igf-1 Isoforms On Muscle Growth And Sarcopenia., Francesca Ascenzi, Laura Barberi, Gabriella Dobrowolny, Aline Villa Nova Bacurau, Carmine Nicoletti, Emanuele Rizzuto, Nadia Rosenthal, Bianca Maria Scicchitano, Antonio Musarò Jun 2019

Effects Of Igf-1 Isoforms On Muscle Growth And Sarcopenia., Francesca Ascenzi, Laura Barberi, Gabriella Dobrowolny, Aline Villa Nova Bacurau, Carmine Nicoletti, Emanuele Rizzuto, Nadia Rosenthal, Bianca Maria Scicchitano, Antonio Musarò

Faculty Research 2019

The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin-like growth factor-1 (IGF-1) has been implicated in many anabolic pathways in skeletal muscle. IGF-1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF-1Ea and IGF-1Eb ...


The Genome Of C57bl/6j "Eve", The Mother Of The Laboratory Mouse Genome Reference Strain., Vishal Kumar Sarsani, Narayanan Raghupathy, Ian T Fiddes, Joel Armstrong, Francoise Thibaud-Nissen, Oraya Zinder, Mohan Bolisetty, Kerstin Howe, Doug Hinerfeld, Xiaoan Ruan, Lucy B. Rowe, Mary Barter, Guruprasad Ananda, Benedict Paten, George M. Weinstock, Gary Churchill, Michael V. Wiles, Valerie A Schneider, Anuj Srivastava, Laura G Reinholdt Jun 2019

The Genome Of C57bl/6j "Eve", The Mother Of The Laboratory Mouse Genome Reference Strain., Vishal Kumar Sarsani, Narayanan Raghupathy, Ian T Fiddes, Joel Armstrong, Francoise Thibaud-Nissen, Oraya Zinder, Mohan Bolisetty, Kerstin Howe, Doug Hinerfeld, Xiaoan Ruan, Lucy B. Rowe, Mary Barter, Guruprasad Ananda, Benedict Paten, George M. Weinstock, Gary Churchill, Michael V. Wiles, Valerie A Schneider, Anuj Srivastava, Laura G Reinholdt

Faculty Research 2019

Isogenic laboratory mouse strains enhance reproducibility because individual animals are genetically identical. For the most widely used isogenic strain, C57BL/6, there exists a wealth of genetic, phenotypic, and genomic data, including a high-quality reference genome (GRCm38.p6). Now 20 years after the first release of the mouse reference genome, C57BL/6J mice are at least 26 inbreeding generations removed from GRCm38 and the strain is now maintained with periodic reintroduction of cryorecovered mice derived from a single breeder pair, aptly named Adam and Eve. To provide an update to the mouse reference genome that more accurately represents the genome ...


Toward A Comprehensive View Of Cancer Immune Responsiveness: A Synopsis From The Sitc Workshop., Davide Bedognetti, Michele Ceccarelli, Lorenzo Galluzzi, Rongze Lu, Karolina Palucka, Josue Samayoa, Stefani Spranger, Sarah Warren, Kwok-Kin Wong, Elad Ziv, Diego Chowell, Lisa M Coussens, Daniel D De Carvalho, David G Denardo, Jérôme Galon, Howard L Kaufman, Tomas Kirchhoff, Michael T Lotze, Jason J Luke, Andy J Minn, Katerina Politi, Leonard D. Shultz, Richard Simon, Vésteinn Thórsson, Joanne B Weidhaas, Maria Libera Ascierto, Paolo Antonio Ascierto, James M Barnes, Valentin Barsan, Praveen K Bommareddy, Adrian Bot, Sarah E Church, Gennaro Ciliberto, Andrea De Maria, Dobrin Draganov, Winson S Ho, Heather M Mcgee, Anne Monette, Joseph F Murphy, Paola Nisticò, Wungki Park, Maulik Patel, Michael Quigley, Laszlo Radvanyi, Harry Raftopoulos, Nils-Petter Rudqvist, Alexandra Snyder, Randy F Sweis, Sara Valpione, Lisa H Butterfield, Mary L Disis, Bernard A Fox, Alessandra Cesano, Francesco M Marincola May 2019

Toward A Comprehensive View Of Cancer Immune Responsiveness: A Synopsis From The Sitc Workshop., Davide Bedognetti, Michele Ceccarelli, Lorenzo Galluzzi, Rongze Lu, Karolina Palucka, Josue Samayoa, Stefani Spranger, Sarah Warren, Kwok-Kin Wong, Elad Ziv, Diego Chowell, Lisa M Coussens, Daniel D De Carvalho, David G Denardo, Jérôme Galon, Howard L Kaufman, Tomas Kirchhoff, Michael T Lotze, Jason J Luke, Andy J Minn, Katerina Politi, Leonard D. Shultz, Richard Simon, Vésteinn Thórsson, Joanne B Weidhaas, Maria Libera Ascierto, Paolo Antonio Ascierto, James M Barnes, Valentin Barsan, Praveen K Bommareddy, Adrian Bot, Sarah E Church, Gennaro Ciliberto, Andrea De Maria, Dobrin Draganov, Winson S Ho, Heather M Mcgee, Anne Monette, Joseph F Murphy, Paola Nisticò, Wungki Park, Maulik Patel, Michael Quigley, Laszlo Radvanyi, Harry Raftopoulos, Nils-Petter Rudqvist, Alexandra Snyder, Randy F Sweis, Sara Valpione, Lisa H Butterfield, Mary L Disis, Bernard A Fox, Alessandra Cesano, Francesco M Marincola

Faculty Research 2019

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes ...


Acetate Promotes T Cell Effector Function During Glucose Restriction., Jing Qiu, Matteo Villa, David E Sanin, Michael D Buck, David O'Sullivan, Reagan Ching, Mai Matsushita, Katarzyna M Grzes, Frances Winkler, Chih-Hao Chang, Jonathan D Curtis, Ryan L Kyle, Nikki Van Teijlingen Bakker, Mauro Corrado, Fabian Haessler, Francesca Alfei, Joy Edwards-Hicks, Leonard B Maggi, Dietmar Zehn, Takeshi Egawa, Bertram Bengsch, Ramon I Klein Geltink, Thomas Jenuwein, Edward J Pearce, Erika L Pearce May 2019

Acetate Promotes T Cell Effector Function During Glucose Restriction., Jing Qiu, Matteo Villa, David E Sanin, Michael D Buck, David O'Sullivan, Reagan Ching, Mai Matsushita, Katarzyna M Grzes, Frances Winkler, Chih-Hao Chang, Jonathan D Curtis, Ryan L Kyle, Nikki Van Teijlingen Bakker, Mauro Corrado, Fabian Haessler, Francesca Alfei, Joy Edwards-Hicks, Leonard B Maggi, Dietmar Zehn, Takeshi Egawa, Bertram Bengsch, Ramon I Klein Geltink, Thomas Jenuwein, Edward J Pearce, Erika L Pearce

Faculty Research 2019

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in ...


Cleaning Genotype Data From Diversity Outbred Mice., Karl W Broman, Daniel M. Gatti, Karen L. Svenson, Śaunak Sen, Gary Churchill May 2019

Cleaning Genotype Data From Diversity Outbred Mice., Karl W Broman, Daniel M. Gatti, Karen L. Svenson, Śaunak Sen, Gary Churchill

Faculty Research 2019

Data cleaning is an important first step in most statistical analyses, including efforts to map the genetic loci that contribute to variation in quantitative traits. Here we illustrate approaches to quality control and cleaning of array-based genotyping data for multiparent populations (experimental crosses derived from more than two founder strains), using MegaMUGA array data from a set of 291 Diversity Outbred (DO) mice. Our approach employs data visualizations that can reveal problems at the level of individual mice or with individual SNP markers. We find that the proportion of missing genotypes for each mouse is an effective indicator of sample ...


Exercise Prevents Obesity-Induced Cognitive Decline And White Matter Damage In Mice., Leah C. Graham, Weronika Grabowska, Yoona Chun, Shannon L Risacher, Vivek M. Philip, Andrew J Saykin, Alzheimer's Disease Neuroimaging Initiative, Stacey J Sukoff Rizzo, Gareth R Howell May 2019

Exercise Prevents Obesity-Induced Cognitive Decline And White Matter Damage In Mice., Leah C. Graham, Weronika Grabowska, Yoona Chun, Shannon L Risacher, Vivek M. Philip, Andrew J Saykin, Alzheimer's Disease Neuroimaging Initiative, Stacey J Sukoff Rizzo, Gareth R Howell

Faculty Research 2019

Obesity in the western world has reached epidemic proportions, and yet the long-term effects on brain health are not well understood. To address this, we performed transcriptional profiling of brain regions from a mouse model of western diet (WD)-induced obesity. Both the cortex and hippocampus from C57BL/6J (B6) mice fed either a WD or a control diet from 2 months of age to 12 months of age (equivalent to midlife in a human population) were profiled. Gene set enrichment analyses predicted that genes involved in myelin generation, inflammation, and cerebrovascular health were differentially expressed in brains from WD-fed ...


Mouse Genome-Wide Association And Systems Genetics Identifies Lhfp As A Regulator Of Bone Mass., Larry D Mesner, Gina M Calabrese, Basel Al-Barghouthi, Daniel M. Gatti, John P Sundberg, Gary A Churchill, Dana A Godfrey, Cheryl L Ackert-Bicknell, Charles R Farber May 2019

Mouse Genome-Wide Association And Systems Genetics Identifies Lhfp As A Regulator Of Bone Mass., Larry D Mesner, Gina M Calabrese, Basel Al-Barghouthi, Daniel M. Gatti, John P Sundberg, Gary A Churchill, Dana A Godfrey, Cheryl L Ackert-Bicknell, Charles R Farber

Faculty Research 2019

Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P = 3.1 x 10-12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two separate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a ...


Significant Strain Variation In The Mutation Spectra Of Inbred Laboratory Mice., Beth L Dumont May 2019

Significant Strain Variation In The Mutation Spectra Of Inbred Laboratory Mice., Beth L Dumont

Faculty Research 2019

Mutation provides the ultimate source of all new alleles in populations, including variants that cause disease and fuel adaptation. Recent whole genome sequencing studies have uncovered variation in the mutation rate among individuals and differences in the relative frequency of specific nucleotide changes (the mutation spectrum) between populations. Although parental age is a major driver of differences in overall mutation rate among individuals, the causes of variation in the mutation spectrum remain less well understood. Here, I use high-quality whole genome sequences from 29 inbred laboratory mouse strains to explore the root causes of strain variation in the mutation spectrum ...