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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 ...


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 ...


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 ...


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 ...


Fibronectin-Conjugated Thermoresponsive Nanobridges Generate Three Dimensional Human Pluripotent Stem Cell Cultures For Differentiation Towards The Neural Lineages., Linda Harkness, Xiaoli Chen, Zhongfan Jia, Anthony M Davies, Michael Monteiro, Peter Gray, Martin Pera Apr 2019

Fibronectin-Conjugated Thermoresponsive Nanobridges Generate Three Dimensional Human Pluripotent Stem Cell Cultures For Differentiation Towards The Neural Lineages., Linda Harkness, Xiaoli Chen, Zhongfan Jia, Anthony M Davies, Michael Monteiro, Peter Gray, Martin Pera

Faculty Research 2019

Production of 3-dimensional neural progenitor cultures from human pluripotent stem cells offers the potential to generate large numbers of cells. We utilised our nanobridge system to generate 3D hPSC aggregates for differentiation towards the neural lineage, and investigate the ability to passage aggregates while maintaining cells at a stem/progenitor stage. Over 38 days, aggregate cultures exhibited upregulation and maintenance of neural-associated markers and demonstrated up to 10 fold increase in cell number. Aggregates undergoing neural induction in the presence or absence of nanobridges demonstrated no differences in marker expression, proliferation or viability. However, aggregates formed without nanobridges were statistically ...


Integration Of Heterogeneous Functional Genomics Data In Gerontology Research To Find Genes And Pathway Underlying Aging Across Species., Jason A. Bubier, George L Sutphin, Timothy J Reynolds, Ron Korstanje, Axis Fuksman-Kumpa, Erich J Baker, Michael A Langston, Elissa J Chesler Apr 2019

Integration Of Heterogeneous Functional Genomics Data In Gerontology Research To Find Genes And Pathway Underlying Aging Across Species., Jason A. Bubier, George L Sutphin, Timothy J Reynolds, Ron Korstanje, Axis Fuksman-Kumpa, Erich J Baker, Michael A Langston, Elissa J Chesler

Faculty Research 2019

Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data from functional genomics studies of aging. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets ...


Identification Of A Novel Gene Regulating Amygdala-Mediated Fear Extinction., Ozge Gunduz-Cinar, Emma Brockway, Lauren Lederle, Troy Wilcox, Lindsay R Halladay, Ying Ding, Hyunjung Oh, Erica F Busch, Katie Kaugars, Shaun Flynn, Aaron Limoges, Olena Bukalo, Kathryn P Macpherson, Sophie Masneuf, Courtney Pinard, Etienne Sibille, Elissa J Chesler, Andrew Holmes Apr 2019

Identification Of A Novel Gene Regulating Amygdala-Mediated Fear Extinction., Ozge Gunduz-Cinar, Emma Brockway, Lauren Lederle, Troy Wilcox, Lindsay R Halladay, Ying Ding, Hyunjung Oh, Erica F Busch, Katie Kaugars, Shaun Flynn, Aaron Limoges, Olena Bukalo, Kathryn P Macpherson, Sophie Masneuf, Courtney Pinard, Etienne Sibille, Elissa J Chesler, Andrew Holmes

Faculty Research 2019

Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal ...


Human Nk Cell Development In Hil-7 And Hil-15 Knockin Nod/Scid/Il2rgko Mice., Masashi Matsuda, Rintaro Ono, Tomonori Iyoda, Takaho Endo, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Yoriko Saito, Akiko Kaneko, Kanako Shimizu, Daisuke Yamada, Narumi Ogonuki, Takashi Watanabe, Manabu Nakayama, Yoko Koseki, Fuyuko Kezuka-Shiotani, Takanori Hasegawa, Hiromasa Yabe, Shunichi Kato, Atsuo Ogura, Leonard D. Shultz, Osamu Ohara, Masaru Taniguchi, Haruhiko Koseki, Shin-Ichiro Fujii, Fumihiko Ishikawa Apr 2019

Human Nk Cell Development In Hil-7 And Hil-15 Knockin Nod/Scid/Il2rgko Mice., Masashi Matsuda, Rintaro Ono, Tomonori Iyoda, Takaho Endo, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Yoriko Saito, Akiko Kaneko, Kanako Shimizu, Daisuke Yamada, Narumi Ogonuki, Takashi Watanabe, Manabu Nakayama, Yoko Koseki, Fuyuko Kezuka-Shiotani, Takanori Hasegawa, Hiromasa Yabe, Shunichi Kato, Atsuo Ogura, Leonard D. Shultz, Osamu Ohara, Masaru Taniguchi, Haruhiko Koseki, Shin-Ichiro Fujii, Fumihiko Ishikawa

Faculty Research 2019

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies ...


Acarbose Improves Health And Lifespan In Aging Het3 Mice., David E Harrison, Randy Strong, Silvestre Alavez, Clinton M Astle, John Digiovanni, Elizabeth Fernandez, Kevin Flurkey, Michael Garratt, Jonathan A L Gelfond, Martin A Javors, Moshe Levi, Gordon J Lithgow, Francesca Macchiarini, James F Nelson, Stacey J Sukoff Rizzo, Thomas J Slaga, Timothy M Stearns, John Erby Wilkinson, Richard A Miller Apr 2019

Acarbose Improves Health And Lifespan In Aging Het3 Mice., David E Harrison, Randy Strong, Silvestre Alavez, Clinton M Astle, John Digiovanni, Elizabeth Fernandez, Kevin Flurkey, Michael Garratt, Jonathan A L Gelfond, Martin A Javors, Moshe Levi, Gordon J Lithgow, Francesca Macchiarini, James F Nelson, Stacey J Sukoff Rizzo, Thomas J Slaga, Timothy M Stearns, John Erby Wilkinson, Richard A Miller

Faculty Research 2019

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th ...


Identification Of A Functional Non-Coding Variant In The Gaba, Megan K Mulligan, Timothy Abreo, Sarah M Neuner, Cory Parks, Christine E Watkins, M Trevor Houseal, Thomas M Shapaker, Michael Hook, Haiyan Tan, Xusheng Wang, Jesse Ingels, Junmin Peng, Lu Lu, Catherine Kaczorowski, Camron D Bryant, Gregg E Homanics, Robert W Williams Mar 2019

Identification Of A Functional Non-Coding Variant In The Gaba, Megan K Mulligan, Timothy Abreo, Sarah M Neuner, Cory Parks, Christine E Watkins, M Trevor Houseal, Thomas M Shapaker, Michael Hook, Haiyan Tan, Xusheng Wang, Jesse Ingels, Junmin Peng, Lu Lu, Catherine Kaczorowski, Camron D Bryant, Gregg E Homanics, Robert W Williams

Faculty Research 2019

GABA type-A (GABA-A) receptors containing the α2 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to ...


Robust Mouse Tracking In Complex Environments Using Neural Networks., Brian Q Geuther, Sean P Deats, Kai J Fox, Stephen A Murray, Robert E Braun, Jacqueline K White, Elissa J Chesler, Cathleen Lutz, Vivek Kumar Mar 2019

Robust Mouse Tracking In Complex Environments Using Neural Networks., Brian Q Geuther, Sean P Deats, Kai J Fox, Stephen A Murray, Robert E Braun, Jacqueline K White, Elissa J Chesler, Cathleen Lutz, Vivek Kumar

Faculty Research 2019

The ability to track animals accurately is critical for behavioral experiments. For video-based assays, this is often accomplished by manipulating environmental conditions to increase contrast between the animal and the background in order to achieve proper foreground/background detection (segmentation). Modifying environmental conditions for experimental scalability opposes ethological relevance. The biobehavioral research community needs methods to monitor behaviors over long periods of time, under dynamic environmental conditions, and in animals that are genetically and behaviorally heterogeneous. To address this need, we applied a state-of-the-art neural network-based tracker for single mice. We compare three different neural network architectures across visually diverse ...


Factors That Influence Response Classifications In Chemotherapy Treated Patient-Derived Xenografts (Pdx)., Joan Malcolm, Timothy M Stearns, Susan Airhart, Joel H. Graber, Carol J Bult Mar 2019

Factors That Influence Response Classifications In Chemotherapy Treated Patient-Derived Xenografts (Pdx)., Joan Malcolm, Timothy M Stearns, Susan Airhart, Joel H. Graber, Carol J Bult

Faculty Research 2019

In this study, we investigated the impact of initial tumor volume, rate of tumor growth, cohort size, study duration, and data analysis method on chemotherapy treatment response classifications in patient-derived xenografts (PDXs). The analyses were conducted on cisplatin treatment response data for 70 PDX models representing ten cancer types with up to 28-day study duration and cohort sizes of 3-10 tumor-bearing mice. The results demonstrated that a 21-day dosing study using a cohort size of eight was necessary to reliably detect responsive models (i.e., tumor volume ratio of treated animals to control between 0.1 and 0.42)-independent ...


Genomic Inversions And Golga Core Duplicons Underlie Disease Instability At The 15q25 Locus., Flavia A M Maggiolini, Stuart Cantsilieris, Pietro D'Addabbo, Michele Manganelli, Bradley P Coe, Beth L Dumont, Ashley D Sanders, Andy Wing Chun Pang, Mitchell R Vollger, Orazio Palumbo, Pietro Palumbo, Maria Accadia, Massimo Carella, Evan E Eichler, Francesca Antonacci Mar 2019

Genomic Inversions And Golga Core Duplicons Underlie Disease Instability At The 15q25 Locus., Flavia A M Maggiolini, Stuart Cantsilieris, Pietro D'Addabbo, Michele Manganelli, Bradley P Coe, Beth L Dumont, Ashley D Sanders, Andy Wing Chun Pang, Mitchell R Vollger, Orazio Palumbo, Pietro Palumbo, Maria Accadia, Massimo Carella, Evan E Eichler, Francesca Antonacci

Faculty Research 2019

Human chromosome 15q25 is involved in several disease-associated structural rearrangements, including microdeletions and chromosomal markers with inverted duplications. Using comparative fluorescence in situ hybridization, strand-sequencing, single-molecule, real-time sequencing and Bionano optical mapping analyses, we investigated the organization of the 15q25 region in human and nonhuman primates. We found that two independent inversions occurred in this region after the fission event that gave rise to phylogenetic chromosomes XIV and XV in humans and great apes. One of these inversions is still polymorphic in the human population today and may confer differential susceptibility to 15q25 microdeletions and inverted duplications. The inversion breakpoints ...


Toward Regeneration Of The Heart: Bioengineering Strategies For Immunomodulation., Arianna Ferrini, Molly M Stevens, Susanne Sattler, Nadia Rosenthal Mar 2019

Toward Regeneration Of The Heart: Bioengineering Strategies For Immunomodulation., Arianna Ferrini, Molly M Stevens, Susanne Sattler, Nadia Rosenthal

Faculty Research 2019

Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF ...


Combined Congenic Mapping And Nuclease-Based Gene Targeting For Studying Allele-Specific Effects Of Tnfrsf9 Within The Idd9.3 Autoimmune Diabetes Locus., Matthew H Forsberg, Bardees Foda, David V. Serreze, Yi-Guang Chen Mar 2019

Combined Congenic Mapping And Nuclease-Based Gene Targeting For Studying Allele-Specific Effects Of Tnfrsf9 Within The Idd9.3 Autoimmune Diabetes Locus., Matthew H Forsberg, Bardees Foda, David V. Serreze, Yi-Guang Chen

Faculty Research 2019

Rodent complex trait genetic studies involving a cross between two inbred strains are usually followed by congenic mapping to refine the loci responsible for the phenotype. However, progressing from a chromosomal region to the actual causal gene remains challenging because multiple polymorphic genes are often closely linked. The goal of this study was to develop a strategy that allows candidate gene testing by allele-specific expression without prior knowledge of the credible causal variant. Tnfrsf9 (encoding CD137) is a candidate gene for the Idd9.3 type 1 diabetes (T1D) susceptibility locus in the nonobese diabetic (NOD) mouse model. A C57BL/10Sn ...


Quantitative Evaluation Of Ontology Design Patterns For Combining Pathology And Anatomy Ontologies., Sarah M Alghamdi, Beth A. Sundberg, John P Sundberg, Paul N Schofield, Robert Hoehndorf Mar 2019

Quantitative Evaluation Of Ontology Design Patterns For Combining Pathology And Anatomy Ontologies., Sarah M Alghamdi, Beth A. Sundberg, John P Sundberg, Paul N Schofield, Robert Hoehndorf

Faculty Research 2019

Data are increasingly annotated with multiple ontologies to capture rich information about the features of the subject under investigation. Analysis may be performed over each ontology separately, but recently there has been a move to combine multiple ontologies to provide more powerful analytical possibilities. However, it is often not clear how to combine ontologies or how to assess or evaluate the potential design patterns available. Here we use a large and well-characterized dataset of anatomic pathology descriptions from a major study of aging mice. We show how different design patterns based on the MPATH and MA ontologies provide orthogonal axes ...


Cardiac Phenotype In Mouse Models Of Systemic Autoimmunity., Chandan Sanghera, Lok Man Wong, Mona Panahi, Amalia Sintou, Muneer G. Hasham, Susanne Sattler Mar 2019

Cardiac Phenotype In Mouse Models Of Systemic Autoimmunity., Chandan Sanghera, Lok Man Wong, Mona Panahi, Amalia Sintou, Muneer G. Hasham, Susanne Sattler

Faculty Research 2019

Patients suffering from systemic autoimmune diseases are at significant risk of cardiovascular complications. This can be due to systemically increased levels of inflammation leading to accelerated atherosclerosis, or due to direct damage to the tissues and cells of the heart. Cardiac complications include an increased risk of myocardial infarction, myocarditis and dilated cardiomyopathy, valve disease, endothelial dysfunction, excessive fibrosis, and bona fide autoimmune-mediated tissue damage by autoantibodies or auto-reactive cells. There is, however, still a considerable need to better understand how to diagnose and treat cardiac complications in autoimmune patients. A range of inducible and spontaneous mouse models of systemic ...