Life Sciences Commons^™

Genetic Perturbations Of Disease Risk Genes In Mice Capture Transcriptomic Signatures Of Late-Onset Alzheimer's Disease., Ravi S Pandey, Leah C. Graham, Asli Uyar, Christoph Preuss, Gareth R Howell, Gregory W. Carter

Faculty Research 2019

BACKGROUND: New genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer's disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.

METHODS: We performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; …

Interleukin-27 Is Essential For Type 1 Diabetes Development And Sjögren Syndrome-Like Inflammation., Ashley E Ciecko, Bardees Foda, Jennifer Y Barr, Sheela Ramanathan, Mark A Atkinson, David V. Serreze, Aron M Geurts, Scott M Lieberman, Yi-Guang Chen

Faculty Research 2019

Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27^-/- and NOD.Il27ra^-/- strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity …

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 …

The Alliance Of Genome Resources: Building A Modern Data Ecosystem For Model Organism Databases., Alliance Of Genome Resources Consortium, Carol J Bult, Judith A. Blake, Brian R Calvi, J. Michael Cherry, Valentina Difrancesco, Robert Fullem, Kevin L Howe, Thom Kaufman, Chris Mungall, Norbert Perrimon, Mary Shimoyama, Paul W Sternberg, Paul Thomas, Monte Westerfield

Faculty Research 2019

Model organisms are essential experimental platforms for discovering gene functions, defining protein and genetic networks, uncovering functional consequences of human genome variation, and for modeling human disease. For decades, researchers who use model organisms have relied on Model Organism Databases (MODs) and the Gene Ontology Consortium (GOC) for expertly curated annotations, and for access to integrated genomic and biological information obtained from the scientific literature and public data archives. Through the development and enforcement of data and semantic standards, these genome resources provide rapid access to the collected knowledge of model organisms in human readable and computation-ready formats that would …

The Jax Synteny Browser For Mouse-Human Comparative Genomics., Georgi Kolishovski, Anna Lamoureux, Paul Hale, Joel E Richardson, Jill M. Recla, Omoluyi Adesanya, Allen K. Simons, Govindarajan Kunde-Ramamoorthy, Carol J Bult

Faculty Research 2019

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the …

The Genetics Of Neuropathic Pain From Model Organisms To Clinical Application., Margarita Calvo, Alexander J Davies, Harry L Hébert, Greg A Weir, Elissa J Chesler, Nanna B Finnerup, Roy C Levitt, Blair H Smith, G Gregory Neely, Michael Costigan, David L Bennett

Faculty Research 2019

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and …

A Bayesian Mixture Model For The Analysis Of Allelic Expression In Single Cells., Kwangbom Choi, Narayanan Raghupathy, Gary Churchill

Faculty Research 2019

Allele-specific expression (ASE) at single-cell resolution is a critical tool for understanding the stochastic and dynamic features of gene expression. However, low read coverage and high biological variability present challenges for analyzing ASE. We demonstrate that discarding multi-mapping reads leads to higher variability in estimates of allelic proportions, an increased frequency of sampling zeros, and can lead to spurious findings of dynamic and monoallelic gene expression. Here, we report a method for ASE analysis from single-cell RNA-Seq data that accurately classifies allelic expression states and improves estimation of allelic proportions by pooling information across cells. We further demonstrate that combining …

Transcriptional Profiling Predicts Running Promotes Cerebrovascular Remodeling In Young But Not Midlife Mice., Kate E Foley, Hongtian Stanley Yang, Leah C. Graham, Gareth R Howell

Faculty Research 2019

BACKGROUND: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer's disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood.

RESULTS: To better understand the effects of …

Therapeutic Administration Of Tregitope-Human Albumin Fusion With Insulin Peptides To Promote Antigen-Specific Adaptive Tolerance Induction., Anne S De Groot, Gail Skowron, James Robert White, Christine Boyle, Guilhem Richard, David V. Serreze, William D Martin

Faculty Research 2019

Type 1 Diabetes (T1D) is an autoimmune disease that is associated with effector T cell (Teff) destruction of insulin-producing pancreatic beta-islet cells. Among the therapies being evaluated for T1D is the restoration of regulatory T cell (Treg) activity, specifically directed toward down-modulation of beta-islet antigen-specific T effector cells. This is also known as antigen-specific adaptive tolerance induction for T1D (T1D ASATI). Tregitopes (T regulatory cell epitopes) are natural T cell epitopes derived from immunoglobulin G (IgG) that were identified in 2008 and have been evaluated in several autoimmune disease models. In the T1D ASATI studies presented here, Tregitope peptides were …

Cisplatin-Resistant Triple-Negative Breast Cancer Subtypes: Multiple Mechanisms Of Resistance., David P. Hill, Akeena Harper, Joan Malcolm, Monica Mcandrews, Susan Mockus, Sara E. Patterson, Timothy Reynolds, Erich J Baker, Carol J Bult, Elissa J Chesler, Judith A. Blake

Faculty Research 2019

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies.

METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated …

Genetic Background Modifies Cns-Mediated Sensorimotor Decline In The Ad-Bxd Mouse Model Of Genetic Diversity In Alzheimer's Disease., Kristen M S O'Connell, Andrew R Ouellette, Sarah M Neuner, Amy R Dunn, Catherine Kaczorowski

Faculty Research 2019

Many patients with Alzheimer's dementia (AD) also exhibit noncognitive symptoms such as sensorimotor deficits, which can precede the hallmark cognitive deficits and significantly impact daily activities and an individual's ability to live independently. However, the mechanisms underlying sensorimotor dysfunction in AD and their relationship with cognitive decline remains poorly understood, due in part to a lack of translationally relevant animal models. To address this, we recently developed a novel model of genetic diversity in Alzheimer's disease, the AD-BXD genetic reference panel. In this study, we investigated sensorimotor deficits in the AD-BXDs and the relationship to cognitive decline in these mice. …

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 Npc1^nmf164 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

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

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 fat diets. …

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 been described in these substrains. …

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 mast …

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

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

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

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 large …

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

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 WD-induced inflammation …

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 biomarkers. Linear …

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 combination of …

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 characteristics …

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

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 identifying somatic mutations …

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

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 identified …

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 …