Discoveries – Page 5 – Discovery and Innovation at University of Utah Health

October 12, 2017May 26, 2021

Viral RNA Modulation of Host Gene Expression

Model of viral HSUR2 RNA function. HSUR2 base-pairs with both host target mRNAs and miRNAs (miR-142-3p and miR-16), tethering them together and inhibiting target mRNA stability and expression.

Viruses depend on and modulate their hosts’ cellular environments to maximize replication. Studies of viruses can therefore reveal important aspects of host-pathogen interactions and fundamental cell biology. Viruses often modulate host pathways using proteins, but can also express non-coding RNAs whose functions and mechanisms are mostly unknown.

Cazalla and colleagues studied the small RNAs from H. saimiri, a herpesvirus that establishes latency in the T cells of New World primates and can cause aggressive leukemias and lymphomas in non-natural hosts. They showed these RNAs, called HSURs, modulate host gene expression and inhibit host cell death using a novel mechanism in which the HSURs inhibit host mRNAs by tethering them to host miRNAs and the associated degradation and translation inhibition machinery. This mechanism is a completely novel process, not previously observed in cells, and but which promises to lead to a fuller understanding of gene regulation in both infected and uninfected cells.

References:

A viral Sm-class RNA base-pairs with mRNAs and recruits microRNAs to inhibit apoptosis. Gorbea C, Mosbruger T, Cazalla D. Nature. 2017 Oct;550(7675):275.

Press Releases and Media:

University of Utah Health: A Viral “Bait and Switch” Boosts Infection

Science Signaling Papers of Note

Viral RNA Modulation of Host Gene Expression | PI: Demian Cazalla, PhD

September 5, 2017May 26, 2021

Mechanism of Cold-induced Thermogenesis

Acylcarnitines (AC) boost body heat to adapt to the cold. (Paula Temblador)

Cold-induced thermogenesis is an energy-demanding process that protects warm-blooded animals against reductions in ambient temperature. Villanueva and colleagues demonstrated that in response to cold, the liver switches metabolism to provide acylcarnitines, which are used as fuel by brown fat. Exogenous L-carnitine also rescues the cold sensitivity seen with aging. Thus, this study uncovered an elegant mechanism whereby white adipose tissue provides long-chain fatty acids for hepatic carnitylation and generates plasma acylcarnitines that are used as a fuel source in peripheral tissues.

Judith Simcox, Ph.D., James Cox, Ph.D., Claudio Villanueva, Ph.D.

References:

Global analysis of plasma lipids identifies liver-derived acylcarnitines as a fuel source for brown fat thermogenesis. Simcox J, Geoghegan G, Maschek JA, Bensard CL, Pasquali M, Miao R, Lee S, Jiang L, Huck I, Kershaw EE, Donato AJ, Apte U, Longo N, Rutter J, Schreiber R, Zechner R, Cox J, Villanueva CJ. Cell Metabolism. 2017 Sep;26(3):509.

Press Releases and Media:

University of Utah Health: Boosting a Lipid Fuel Makes Mice Less Sensitive to the Cold.

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Mechanism of Cold-induced Thermogenesis | PI: Claudio J. Villanueva, PhD

June 19, 2017May 26, 2021

Function of a Gene Linked to Autism

Image of a fluorescently labeled mossy fiber synapse from a mouse brain.

Genetic studies have linked autism in humans to dysregulation of synaptic function and altered neural connectivity. Kirrel3 is a key but unstudied autism susceptibility gene. Williams and colleagues discovered that the Kirrel3 gene is necessary to form one part of a massive synaptic complex called the mossy fiber synapse. Kirrel3 is responsible for forming the part of the synapse that turns on inhibitory neurons.

These synapses govern the balance of neuronal activity in the hippocampus, a structure critical for learning and memory. Therefore, without proper Kirrel3 function, the balance of neuronal activity is tipped such that hippocampal neurons are overactive. This work is the first insight into the function of this important disease gene. The Williams lab continues to focus on understanding how specific mutations in Kirrel3 found in patients with autism and intellectual disabilities alter Kirrel3’s function in the brain.

References:

The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus. Martin EA, Muralidhar S, Wang Z, Cervantes DC, Basu R, Taylor MR, Hunter J, Cutforth T, Wilke SA, Ghosh A, Williams ME. Elife. 2015 Nov 17;4:e09395.

Examining hippocampal mossy fiber synapses by 3D electron microscopy in wildtype and Kirrel3 knockout mice. Martin EA, Woodruff D, Rawson RL, Williams ME. eNeuro. 2017 May-Jun;4(3:ENEURO.0088-17.2017.

Press Releases and Media:

University of Utah Health: “Studying Genetic Mutations Linked to Autism Spectrum Disorder”

Function of a Gene Linked to Autism | PI: Megan E. Williams, PhD

June 5, 2017June 28, 2021

Individualized Venous Thromboembolism Risk Stratification and Chemoprophylaxis in Surgical Patients

Venous thromboembolism (VTE) can occur following a surgical procedure, and is usually prevented using anticoagulant chemoprophylaxis. The risk/benefit ratio of chemoprophylaxis, however, varies among individual patients; surgical patients at low risk for VTE may not benefit from chemoprophylaxis, but still be subjected to the bleeding risk. The research team of Christopher Pannucci, MD, and Benjamin Brooke, MD, set out to determine whether chemoprophylaxis for VTE among surgical patients could be better achieved through individualized risk stratification using established Caprini scores. They performed a meta-analysis of nearly 15,000 surgery patients, stratified by Caprini scores for VTE risk levels. When chemoprophylaxis was provided peri-operatively, high-risk patients (Caprini scores >7) exhibited significant VTE risk-reduction without significant increase in bleeding. In comparison, 75% of low-risk patients (Caprini scores <6) had an unfavorable risk/benefit ratio and, therefore, chemoprophylaxis was unwarranted. This study highlights the benefits of a precision-medicine (i.e., risk-stratification) approach to VTE prevention and has important practice implications.

References:

Inadequate venous thromboembolism risk stratification predicts venous thromboembolic events in surgical intensive care unit patients. Pannucci CJ, Obi A, Alvarez R, Abdullah N, Nackashi A, Hu HM, Bahl V, Henke PK. J Am Coll Surg. 2014 May;218(5):898.

Evidence-based recipes for venous thromboembolism prophylaxis: a practical safety guide. Pannucci CJ. Plast Reconstr Surg. 2017 Feb;139(2):520e.

Individualized venous thromboembolism risk stratification using the 2005 Caprini score to identify the benefits and harms of chemoprophylaxis in surgical patients: a meta-analysis. Pannucci CJ, Swistun L, MacDonald JK, Henke PK, Brooke BS. Ann Surg. 2017 Jun;265(6):1094.

Press Releases and Media:

University of Utah Health: “Standard of Care Anti-Clotting Drugs May Be Unnecessary for Most Surgery Patients”

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U of U Health Key Faculty Collaborators

Christopher J. Pannucci, MD

Individualized Venous Thromboembolism Risk Stratification and Chemoprophylaxis in Surgical Patients | PI: Benjamin Brooke, MD

June 1, 2017May 26, 2021

Genes Responsible for Maintaining Embryonic Developmental Potential

Discovery of Dux/DUX4 as a major driver of cleavage-stage genes and processes in mammalian embryos.

A major question concerning early embryos involves how early cleavage-stage (two-cell) embryos establish unlimited developmental potential – termed totipotency. Cairns and colleagues identified the multicopy retrogene, DUX4 in humans or Dux in mice, as a transcription factor that is turned on in very early embryos and activates hundreds of genes and retroviral elements during cleavage stage. Remarkably, the expression of Dux efficiently converts mouse embryonic stem cells into 2-cell-embryo-like cells (2CLC) with expanded developmental potential.

Interestingly, these 2CLC can contribute to either embryonic or extra-embryonic (trophectoderm/placenta) cell lineages. Thus, Dux-family proteins appear to play essential roles in determining developmental potential in early embryos. The improper expression of DUX4 underlies the common muscle disease facioscapulohumeral muscular dystrophy (FSHD), and the results from this work provide important and novel information on the typical role of DUX4 that can now be explored in the context of FSHD.

References:

Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Hendrickson PG, Doráis JA, Grow EJ, Whiddon JL, Lim JW, Wike CL, Weaver BD, Pflueger C, Emery BR, Wilcox AL, Nix DA, Peterson CM, Tapscott SJ, Carrell DT, Cairns BR. Nat Genet. 2017 Jun;49(6):925.

Genes Responsible for Maintaining Embryonic Developmental Potential | PI: Bradley R. Cairns, PhD

June 1, 2017May 26, 2021

Rapid Identification of Microbial Pathogens

Taxonomer is the engine behind IDbyDNA’s Explify platform. “A key barrier to adoption of next-generation sequencing for infectious disease testing has been the lack of simple, powerful bioinformatics software to turn the data generated by the sequencer into actionable insights. IDbyDNA’s Explify Platform combined with Illumina’s NGS systems and library preparation creates a powerful, comprehensive infectious disease workflow.” — Kathy Davy, Vice President of Clinical Marketing at Illumina.

The rapid identification of microbial pathogens is critical for timely and successful treatments. Improved capabilities in pathogen identification were the focus of a collaboration between physicians and scientists in the departments of Biomedical Informatics, Human Genetics, and Pathology. The product, a computational tool called Taxonomer, uses innovative algorithmic approaches to take next-generation sequencing reads and rapidly return a list of taxonomically classified organisms.

This tool was used to diagnose the cause of community-acquired pneumonia and has become the cornerstone of a University of Utah startup company IDbyDNA Inc. In March of 2020, Illumina announced a global strategic partnership with IDbyDNA Inc., to bring comprehensive next-generation sequencing-based workflows to the global microbiology market.

References:

Unbiased detection of respiratory viruses by use of RNA sequencing-based metagenomics: a systematic comparison to a commercial PCR panel. Graf EH, Simmon KE, Tardif KD, Hymas W, Flygare S, Eilbeck K, Yandell M, Schlaberg R. J Clin Microbiol. 2016 Apr;54(4):1000.

Taxonomer: an interactive metagenomics analysis portal for universal pathogen detection and host mRNA expression profiling. Flygare S, Simmon K, Miller C, Qiao Y, Kennedy B, Di Sera T, Graf EH, Tardif KD, Kapusta A, Rynearson S, Stockmann C, Queen K, Tong S, Voelkerding KV, Blaschke A, Byington CL, Jain S, Pavia A, Ampofo K, Eilbeck K, Marth G, Yandell M, Schlaberg R. Genome Biol. 2016 May;17(1):111.

Validation of metagenomic next-generation sequencing tests for universal pathogen detection. Schlaberg R, Chiu CY, Miller S, Procop GW, Weinstock G; Professional Practice Committee and Committee on Laboratory Practices of the American Society for Microbiology; Microbiology Resource Committee of the College of American Pathologists. Arch Pathol Lab Med. 2017 Jun;141(6):776.

Press Releases and Media:

University of Utah Health: “Metagenomics Pathogen Detection Tool Could Change How Infectious Diseases Are Diagnosed”

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Rapid Identification of Microbial Pathogens | PI: Robert Schlaberg, MD, Gabor Marth, DSc, Mark Yandell, PhD & Karen Eilbeck, PhD

April 1, 2017June 22, 2021

Therapy for ALS

Amyotrophic lateral sclerosis (ALS) is a catastrophic degeneration of the nervous system with great need for disease-modifying treatments. Stefan Pulst, MD, and his collaborator Daniel Scoles, PhD, were studying a lesser-known but similarly dire condition (spinocerebellar ataxia 2, SCA2) when they identified a gene relevant to both diseases. They generated mice expressing the mutant version of the gene identified as the cause of SCA2 in humans (ataxin-2), and developed an antisense oligonucleotide targeting ataxin-2 to test its effects. The antisense oligonucleotide improved SCA2 in these mice. In humans, ALS is associated with abnormal accumulation of the TDP-43 protein in the brain. ALS mice were therefore generated by inducing increased expression of TDP-43. Deletion of the ataxin-2 gene and administration of the ataxin-2 antisense oligonucleotide each improved survival of these mice, presumably by protecting against TDP-43 toxicity. They recently optimized the ataxin-2 antisense oligonucleotide, which is now being tested in clinical trials. This series of ground-breaking studies offers promise for novel strategies to treat these previously incurable and severely debilitating neurological diseases.

Stefan Pulst, MD and Daniel Scholes, PhD — Stefan Pulst, MD, and Daniel Scoles, PhD. Photo credit: Charlie Ehlert.

References:

Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Scoles DR, Meera P, Schneider M, Paul S, Dansithong W, Figueroa KP, Hung G, Rigo F, Bennett CF, Otis TS, Pulst SM.Nature. 2017 April 20;544(7650):362. doi:10.1038/nature22044.

Therapeutic reduction of ataxin 2 extends lifespan and reduces pathology in TDP-43 mice. Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, Pulst SM, Taylor JP, Rigo F, Gitler AD. Nature. 2017 Apr 20;544(7650):367.

U of U Health Key Faculty Collaborator

Sharan Paul, PhD

Therapy for ALS | PI: Stefan M. Pulst, MD & Daniel R. Scoles, PhD

March 2, 2017May 26, 2021

Maintaining Epithelial Barriers

Discovery of Piezo1 as a channel that senses stretch (cell loss) in epithelial sheets, and then promotes proliferation to add cell numbers.

A vital issue in cell biology is how epithelial sheets provide a barrier while balancing cell growth and death, and withstand the stretching forces that sheets experience in vivo. Among the questions raised is how the number of dying cells is matched by newly dividing cells to maintain consistent numbers. Rosenblatt and colleagues demonstrated that mechanical stretching stimulates epithelial cell division and characterized the stretch-sensitive Piezo1 channel as well as the downstream signaling that triggers cell division.

Mechanistically, they found that stretch triggers cells that are paused in the early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis – causing cell division. Although both epithelial cell division and cell extrusion require Piezo1 channels, the type of mechanical force exerted controls the outcome: stretch induces cell division, whereas crowding induces extrusion.

References:

Mechanical stretch triggers rapid epithelial cell division through Piezo1. Gudipaty SA, Lindblom J, Loftus PD, Redd MJ, Edes K, Davey CF, Krishnegowda V, Rosenblatt J. Nature. 2017 Mar;543(7643):118.

Maintaining Epithelial Barriers | PI: Jody Rosenblatt, PhD

March 1, 2017June 10, 2021

Cancer Symptom Care at Home

Cancer and its treatments cause a variety of symptoms that decrease quality of life and can even be life-threatening. Symptoms such as pain, nausea and vomiting, fever, fatigue, and weakness frequently occur while patients are at home in between their clinic visits. Patients and their family members are often ill-prepared to evaluate and manage these symptoms themselves. As a consequence, poorly controlled symptoms frequently result in emergency department visits and unplanned hospitalizations.

To address this problem, Huntsman Cancer Institute investigator Kathi Mooney, PhD, RN, and her colleague, Susan Beck, PhD, APRN, developed Symptom Care at Home, an automated, remote-monitoring platform that assesses 11 symptoms at home, provides automated self-management coaching based on the symptom severity reported, and automatically alerts the clinical team about symptoms requiring further intervention. An electronic decision support dashboard guides the clinical team in intensifying symptom care based on evidence-based practice guidelines. Tested through randomized controlled trials, this technology-aided solution has resulted in dramatic reductions in patients’ symptoms as well as improvements in the well-being of family caregivers.

References:

Automated home monitoring and management of patient-reported symptoms during chemotherapy: results of the symptom care at home RCT. Mooney K, Beck SL, Wong B, Dunson W, Wujcik D, Whisenant M, Donaldson G. Cancer Med. 2017 Mar;6(3):537-546.

Symptom Care @ Home: developing an integrated symptom monitoring and management system for outpatients receiving chemotherapy. Beck SL, Eaton LH, Echeverria C, Mooney K. Comput Inform Nurs. 2017 Oct;35(10):520-529.

Symptom Care at Home: a comprehensive and pragmatic PRO system approach to improve cancer symptom care. Mooney K, Whisenant MS, Beck SL. Med Care. 2019 May;57 Suppl 5 Suppl 1:S66-S72.

U of U Health Key Faculty Collaborator

Susan L. Beck, PhD

Cancer Symptom Care at Home | PI: Kathi Mooney, PhD, RN

February 13, 2017May 26, 2021

Defining Pathways for Formation and Suppression of Highly Metastatic Lung Tumors

MYC drives a molecular subtype of small cell lung cancer with unique vulnerability to Aurora kinase inhibition.

Cancers arise from the complex interplay of oncogene activation and tumor suppressor inactivation. Loss of the tumor suppressors RB1 and TP53, as well as amplification of the pro-proliferative oncogene MYC, are frequent oncogenic events in small cell lung cancer. There are multiple subtypes of small cell lung cancers, but few targeted therapeutic options for patients. Here, Oliver and colleagues uncovered how Myc cooperates with other oncogene products to promote aggressive, highly metastatic lung tumors. Furthermore, they showed that these tumors are susceptible to Aurora kinase inhibition, indicating a strategy for suppressing tumor progression and increasing survival in patients with this common lung cancer sub-type.

References:

MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG. Cancer Cell. 2017 Feb;31(2):270.

Defining Pathways for Formation and Suppression of Highly Metastatic Lung Tumors | PI: Trudy G. Oliver, PhD

January 25, 2017May 26, 2021

Defining Pathways for Bone Destruction and Preservation in Cancer

A RON Kinase inhibitor reduces bone destruction (CTX marker) and increases bone repair (BSAP marker) in mice. Females (treated), Males (control).

Bone destruction occurs during aging and numerous diseases, such as osteoporosis and cancer. Many cancer patients, including those with breast-to-bone metastasis, have bone osteolysis that is refractory to state-of-the-art treatments. Macrophage-stimulating protein (MSP) signaling, which is elevated in about 40% of breast cancers, promotes osteolytic bone metastasis by activation of the MSP signaling pathway in tumor cells or the bone microenvironment.

Welm and colleagues showed that MSP signals through its receptor, RON tyrosine kinase, which is expressed on the surface of host cells to activate osteoclasts directly by converging on the oncogene SRC. Thus, they have identified RON tyrosine kinase as a viable target for reducing bone loss in patients who have breast-to-bone metastasis and provided proof of this principle in mouse models as well as initial clinical trials.

References:

RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis. Andrade K, Fornetti J, Zhao L, Miller SC, Randall RL, Anderson N, Waltz SE, McHale M, Welm AL. Sci Transl Med. 2017 Jan;9(374). pii: eaai9338.

Defining Pathways for Bone Destruction and Preservation in Cancer | PI: Alana L. Welm, PhD

December 8, 2016May 26, 2021

Designing Proteins to Carry Cargoes Between Cells

Scientists at the University of Utah and University of Washington have designed a self-assembling, biologically-based system that can deliver custom cargo between human cells. Cargo is encased in protein nanocages (yellow, enlarged on left) that are carried from one cell to another within vesicles built from membranes (green, shown in cross-section). Each vesicle can hold multiple cargo-carrying nanocages. **Credit**: David Belnap, Jörg VottelerDesigned protein nanocages released within membrane vesicles.

Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids, and lipids). Approaches have been developed for designing synthetic self-assembling structures consisting of either nucleic acids or proteins, but strategies for engineering hybrid biological materials are only beginning to emerge.

Sundquist, King, Belnap, and colleagues reported the de novo design and characterization of proteins that direct their assembly and release from human cells within membrane vesicles. These virus-inspired delivery systems can also transfer biological cargoes between cells, and therefore represent an essential first step in the development of new synthetic systems for delivering therapeutic cargoes into diseased target cells.

References:

Designed proteins induce the formation of nanocage-containing extracellular vesicles. Votteler J, Ogohara C, Yi S, Hsia Y, Nattermann U, Belnap DM, King NP, Sundquist WI. Nature. 2016 Dec;540(7632):292.

Press Releases and Media:

University of Utah Health: “Virus-Inspired Delivery System Transfers Microscopic Cargo Between Human Cells”

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Designing Proteins to Carry Cargoes Between Cells | PI: Wesley I. Sundquist, PhD

October 12, 2016May 26, 2021

Correcting the Genetic Error in Sickle Cell Disease

Editing of sickle hematopoetic stem/progenitor cells reduces sickle (hbS) and increases normal (hbA) hemoglobin.

The CRISPR/Cas9 DNA editing system offers the potential for revolutionary new treatments of genetic diseases. Pioneering work by Carroll set the stage for this revolution by characterizing how cells detect and repair double-stranded DNA breaks. Sickle cell disease is common among African Americans and widespread in tropical regions of Africa and southern Asia.

Carroll and his colleagues used the CRISPR/Cas9 gene editing system and a novel delivery method to correct the sickle mutation in adult human hematopoietic stem/progenitor cells. Continuing work on this approach has improved the efficiency of correction, and treatment of the first patients is anticipated by the end of 2020.

Dana Carroll, PhD. Photo credit: Charlie Ehlert

References:

Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. DeWitt MA, Magis W, Bray NL, Wang T, Berman JR, Urbinati F, Heo SJ, Mitros T, Muñoz DP, Boffelli D, Kohn DB, Walters MC, Carroll D, Martin DI, Corn JE. Science Translational Medicine. 2016 Oct;8(360):360ra134.

Press Releases and Media:

University of Utah Health: “Genome Engineering Paves the Way for Sickle Cell Cure”

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Correcting the Genetic Error in Sickle Cell Disease | PI: Dana Carroll, PhD

October 3, 2016June 9, 2021

Inhibiting Neutrophil Extracellular Traps (NETs) in Immune Injury and Pathologic Clotting

Deficient or excess immune system activities cause many human diseases. To understand the mechanisms of immune injury and their links to pathologic clotting, University of Utah Health investigators Christian Yost, MD, Guy Zimmerman, MD, and colleagues defined features of neutrophil extracellular traps (NETs). NETs are extracellular lattices of sticky, unwound DNA studded with antimicrobial proteins which are normally released by neutrophils to capture and kill microbes. However, excess NET formation leads to inflammatory injury and clotting in diseases such as sepsis. These researchers also discovered a protein, produced by the placenta, which blocks NET formation. Called neonatal NET-Inhibitory Factor (nNIF), this protein was shown in mouse studies to improve survival of severe infection.

Yost and Zimmerman’s work allowed fellow University of Utah Health investigator Elizabeth Middleton, MD, to respond immediately when COVID-19 struck. Middleton and colleagues identified a connection between NET-related clotting and pneumonia and respiratory failure in patients with COVID-19. They also found that nNIF blocked NET formation in COVID-19 patients’ blood. Thus, by triggering pathological clotting, NET formation may contribute to serious symptoms of severe COVID-19. This discovery highlights NET inhibition as a promising strategy for new therapies.

References:

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. Yost CC, Schwertz H, Cody MJ, Wallace JA, Campbell RA, Vieira-de-Abreu A, Araujo CV, Schubert S, Harris ES, Rowley JW, Rondina MT, Fulcher JM, Koening CL, Weyrich AS, Zimmerman GA. J Clin Invest. 2016 Oct 3;126(10):3783-3798.

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Middleton EA, He XY, Denorme F, Campbell RA, Ng D, Salvatore SP, Mostyka M, Baxter-Stoltzfus A, Borczuk AC, Loda M, Cody MJ, Manne BK, Portier I, Harris ES, Petrey AC, Beswick EJ, Caulin AF, Iovino A, Abegglen LM, Weyrich AS, Rondina MT, Egeblad M, Schiffman JD, Yost CC. Blood. 2020 Sep 3;136(10):1169-1179.

Inhibiting Neutrophil Extracellular Traps (NETs) in Immune Injury and Pathologic Clotting | PI: Christian Con Yost, MD, Guy A. Zimmerman, MD & Elizabeth A. Middleton, MD

June 1, 2016August 14, 2021

Translating Influenza Immunization in Pregnancy into Infant Immunity

Infants with influenza are at increased risk for adverse outcomes, particularly in the first six months when they are unable to mount a sufficient response to influenza immunization. Few large-scale studies have evaluated the impact of maternal immunization during pregnancy on subsequent infant influenza outcomes. To address this gap, Julie Shakib, DO, and colleagues conducted a retrospective cohort study of 245,386 pregnant women and their infants over nine influenza seasons. They found that infants born to women reporting influenza immunization during pregnancy had risk reductions of 70% for influenza infection and 81% for influenza hospitalization in the first six months. The research group is now developing methods to investigate the optimal timing of immunization during pregnancy. This collective body of work aids the development of more targeted influenza-immunization strategies that better protect new mothers and their infants.

References:

Influenza in infants born to women vaccinated during pregnancy. Shakib JH, Korgenski K, Presson AP, Sheng X, Varner MW, Pavia AT, Byington CL. Pediatrics. 2016 Jun;137(6): e20152360.

Press Releases and Media:

University of Utah Health: “Infants Much Less Likely To Get The Flu If Moms Are Vaccinated While Pregnant”

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U of U Health Key Faculty Collaborators

Andrew T. Pavia, MD
Michael W. Varner, MD
Angela P. Presson, PhD
Carrie L. Byington, MD
Xiaoxi Liu, PhD

Translating Influenza Immunization in Pregnancy into Infant Immunity | PI: Julie H. Shakib, DO

April 1, 2016June 28, 2021

The Power of mRNA in Anucleate Platelets

Platelets are the smallest cell in the bloodstream, and one of the few anucleate cells (i.e., cells that circulate without a nucleus). Because of their small size and anucleate stature, platelets have historically been conceived of as “sacs of glue” that function solely to stop bleeding. Andrew Weyrich, MD, and his group made the seminal discovery that anucleate human platelets transform messenger RNA (mRNA) into mature products that code for protein. More recently, his group found that a specific type of microRNAs (Dicer1-dependent) and their precursors (megakaryocytes) modulate the expression of target mRNAs important for cellular function.

These observations revolutionized the field of hematology, leading to an explosion of studies that use mRNA profiling to identify previously-unrecognized functions of megakaryocytes and platelets that regulate thrombosis and inflammation (i.e., thromboinflammation). This work has also advanced scientific understanding of non-traditional functions of platelets that regulate the course of numerous diseases, including cardiovascular disease, diabetes, and infectious syndromes.

References:

Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Denis MM, Tolley ND, Bunting M, Schwertz H, Jiang H, Lindemann S, Yost CC, Rubner FJ, Albertine KH, Swoboda KJ, Fratto CM, Tolley E, Kraiss LW, McIntyre TM, Zimmerman GA, Weyrich AS. Cell. 2005 August 12;122(3):379.

Regulation of the genetic code in megakaryocytes and platelets. Rondina MT, Weyrich AS. J Thromb Haemost. 2015 June; 13 Suppl 1(0 1):S26. PMCID: PMC4498409.

Dicer1 mediated miRNA processing shapes the mRNA profile and function of murine platelets. Rowley JW, Chappaz S, Corduan A, Chong MMW, Campbell RA, Khoury A, Manne BK, Wurtzel JGT, Michael JV, Goldfinger LE, Mumaw MM, Nieman MT, Kile BT, Provost P, Weyrich AS. Blood. 2016 April 7;127(14):1743. PMCID: PMC4825412.

The platelet transcriptome in health and disease. Rowley JW, Weyrich AS, Bray PF. AD Michelson, ed. In Platelets Fourth Edition Elsevier London. 2019:139.

U of U Health Key Faculty Collaborators

Guy A. Zimmerman, MD
Matthew T. Rondina, MD
Jesse Rowley, PhD

The Power of mRNA in Anucleate Platelets | PI: Andrew S. Weyrich, PhD

March 5, 2016June 28, 2021

(Pro)Renin Receptor: A Novel Target for Hypertension, Kidney Disease, and Metabolic Syndrome

Recombinant sPRR ameliorates fatty liver as well as other components of metabolic syndrome in mice with diet-induced obesity. Normal diet (lean); diet-induced obesity (DIO); histidine-tagged sPRR (sPRR-His).

The enzyme renin plays a role in the development of hypertension (high blood pressure), cardiovascular disease, and kidney disease. Studies in mice and rats unexpectedly uncovered other biological activities of the receptor for renin and its precursor, (pro)renin receptor (PRR). University of Utah Health researcher Tianxin Yang, MD, PhD, and colleagues have made a series of new discoveries about the function of PRR. They demonstrated that PRR activation stimulates sodium and water retention by the kidney, causing hypertension; over-activation of PRR also causes kidney damage. Targeting this pathway with a compound that blocks PRR is highly effective in treating hypertension and chronic kidney disease in rodents.

Yang and colleagues also showed that a soluble form of PRR found in the body, sPRR, similarly has multiple functions. In addition to regulating kidneys’ handling of sodium and water, administration of sPRR effectively treats multiple components of metabolic syndrome in mice, including obesity, diabetes, and fatty liver. Yang is now actively developing and testing technologies based on these discoveries to treat various human diseases.

References:

Prostaglandin E-prostanoid4 receptor mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla. Wang F, Lu X, Peng K, Zhou L, Li C, Zhang A, Yang T. Hypertension. 2014 Aug;64(2):369-77.

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor. Lu X, Wang F, Xu C, Soodvilai S, Peng K, Su J, Zhao L, Yang KT, Feng Y, Zhou SF, Gustafsson J-A, Yang T. Proc Natl Acad Sci USA. 2016 Mar 29;113(13):E1898-906.

Antidiuretic action of collecting duct (pro)renin receptor downstream of vasopressin/EP4 receptor. Wang F, Lu X, Peng K, Fang H, Zhou L, Su J, Nau A, Yang K, Ichihara A, Lu A, Zhou SF, Yang T. J Am Soc Nephrol. 2016 Oct;27(10):3022-3034.

Activation of renal (pro)renin receptor contributes to high fructose-induced salt sensitivity. Xu C, Lu A, Lu X, Zhang L, Fang H, Zhou L, Yang T. Hypertension. 2017 Feb;69(2):339-348.

Site-1 protease-derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability. Wang F, Xu C, Luo R, Peng K, Ramkumar N, Xie S, Lu X, Zhao L, Zuo C-J, Kohan DE, Yang T. JCI Insight. 2019 Apr 4;4(7):e124174.

Soluble (pro)renin receptor regulation of ENaC involved in aldosterone signaling in cultured collecting duct cells. Wang F, Luo R, Peng K, Liu X, Xu C, Lu X, Soodvilai S, Yang T. Am J Physiol Renal Physiol. 2020 Mar 1;318(3):F817-F825.

Elabela antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury. Xu C, Wang F, Chen Y, Xie S, Sng D, Reversade B, Yang T. Am J Physiol Renal Physiol. 2020 May 1;318(5):F1122-F1135.

COX-2-independent activation of penal (pro)renin receptor contributes to DOCA-salt hypertension in rats. Wang F, Sun Y, Luo R, Lu X, Yang B, Yang T. Am J Physiol Renal Physiol. 2020 Oct 1;319(4):F647-F653.

Soluble (pro)renin receptor promotes fibrotic response in renal proximal tubule epithelial cells in vitro via Akt/β-catenin/Snail signaling pathway. Xie S, Su J, Lu A, Lai Y, MoS, PuM, Yang T. Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F941-F953.

(Pro)renin receptor decoy peptide PRO20 protects against adriamycin-induced nephropathy by targeting intrarenal renin-angiotensin system. Luo R, Yang K, Wang F, Xu C, Yang T. Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F930-F940.

Site-1 protease-derived soluble (pro)renin receptor contributes to angiotensin II-induced hypertension in mice. Feng Y, Peng K, Luo R, Wang F, Yang T. Hypertension. 2021 Feb;77(2):405-416.

Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor. Fu Z, Wang F, Liu X, Hu J, Su J, Lu X, Lu A, Cho JM, Symons JD, Zou CJ, Yang T. Clin Sci (Lond). 2021 Mar 26;135(6):793-810.

Mutagenesis of the cleavage site of (pro)renin receptor abrogates angiotensin II-induced hypertension in mice. Wang F, Chen Y, Zou C, Luo R, Yang T. Hypertension. In press.

(Pro)Renin Receptor: A Novel Target for Hypertension, Kidney Disease, and Metabolic Syndrome | PI: Tianxin Yang, MD, PhD

March 1, 2016May 26, 2021

Regulation of Innate Immune Pathways

Schematic illustrating how ancient viral DNA elements in our genome have become repurposed to help regulate mammalian immune defenses.

Cells must regulate their innate immune pathways so that they can respond rapidly to pathogens, yet avoid aberrant activation that can lead to inflammation. The evolution of these regulatory mechanisms remains to be understood.

Elde, Feschotte and colleagues demonstrated that endogenous retroviruses, and the promoters that they introduce into the genome, have been co-opted by cells to play critical roles in regulating the innate immune system. Although these regulatory sequences likely arose in ancient viruses, they now constitute a dynamic reservoir of interferon-inducible enhancers that fuel genetic innovation in mammalian immune defenses. Thus, we have turned the tables, and ancient viral DNA has now become important for mounting a proper defense against today’s viral infections.

Three men in front of white board — Cedric Feschotte, PhD, Edward Chuong, PhD, Nels Elde, PhD discuss viral DNA fragments help fight viral infections.

References:

Regulatory evolution of innate immunity through co-option of endogenous retroviruses Chuong EB, Elde NC, Feschotte C. Science. 2016 Mar;351(6277):1083.

Regulatory activities of transposable elements: from conflicts to benefits. Chuong EB, Elde NC, Feschotte C. Nat Rev Genet. 2017 Feb;18(2):71.

Press Releases and Media:

University of Utah Health: Ancient Viral Invaders in Our DNA Help Fight Today’s Infections

New York Times
The Atlantic
Wired
The Smithsonian
Science News
STAT
Genetic Literacy Project
Quartz
Daily Mail
El Pais

Regulation of Innate Immune Pathways | PI: Nels C. Elde, PhD & Cedric Feschotte, PhD

December 18, 2015May 26, 2021

Cellular Membrane Remodeling

ESCRT-III filaments constricting a membrane. (Janet Iwasa)

Cells are continually severing, fusing, and reshaping their membranes. One of the essential cellular membrane remodeling systems is the ESCRT (Endosomal Sorting Complexes Required for Transport) pathway, whose cellular functions include endosomal membrane remodeling, membrane repair, enveloped virus budding, closure of the nuclear envelope, and cytokinetic abscission. Subunits of the ESCRT-III complex perform vital roles in these processes by forming membrane-bound filaments.

To understand how these filaments shape membranes, Frost, Sundquist and colleagues used cryo-EM to determine the first high-resolution structure of an ESCRT-III filament. The structure revealed how ESCRT-III subunits open and interlock in an elaborate domain-swapped filament architecture. Unexpectedly, the results showed that ESCRT-III filaments contain two ESCRT-III strands and that analogous ESCRT-III filament architectures can curve and constrict membranes to different degrees and directions.

References:

Structure and membrane remodeling activity of ESCRT-III helical polymers. McCullough J, Clippinger AK, Talledge N, Skowyra ML, Saunders MG, Naismith TV, Colf LA, Afonine P, Arthur C, Sundquist WI, Hanson PI, Frost A. Science. 2015 Dec;350(6267):1548.

Press Releases and Media:

University of Utah Health: A Molecular Noose Caught in the Act

Cellular Membrane Remodeling | PI: Wesley I. Sundquist, PhD & Adam Frost, PhD

November 5, 2015June 28, 2021

Blood Pressure Treatment Target

Researchers have long debated the optimal blood pressure for people more than 50 years old, especially in older adults who might not tolerate lower blood pressure. Alfred Cheung, MD, and colleagues at University of Utah Health led one of five national Clinical Center Networks to design and conduct the Systolic Blood Pressure Intervention Trial (SPRINT). They examined whether targeting a systolic blood pressure below 120 mm Hg would improve health outcomes compared to targeting systolic blood pressure below 140 mm Hg, previously considered the standard target.

Cheung and colleagues found that intensive blood pressure lowering led to a 25% decrease in major cardiovascular events and all-cause mortality. Adam Bress, PharmD and colleagues determined that the intervention was also economically cost-effective. The cardiovascular and survival benefits extended to people over 75 years old and to individuals with underlying kidney disease or prediabetes, without significant side effects. Additional analyses showed that intensive blood pressure lowering also decreased the combined rate of mild cognitive impairment, including in older adults. This landmark study led to new clinical practice guidelines and changed perceptions of the risk/benefit ratio of intensive blood pressure control in older adults.

References:

A randomized trial of intensive versus standard blood-pressure control. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. N Engl J Med. 2015 Nov;373(22):2103-2116.

Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, Fine LJ, Haley WE, Hawfield AT, Ix JH, et al., SPRINT Research Group. JAMA. 2016 Jun;315(24):2673-2682.

Effect of intensive versus standard blood pressure treatment according to baseline prediabetes status: a post hoc analysis of a randomized trial. Bress AP, King JB, Kreider KE, Beddhu S, Simmons DL, Cheung AK, Zhang Y, Doumas M, Nord J, Sweeney ME, et al., SPRINT Research Group. Diabetes Care. 2017 Aug;40(10):1401–1408.

Effects of intensive BP control in CKD. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, Cushman WC, Hawfield AT, Johnson KC, et al., SPRINT Research Group. J Am Soc Nephrol. 2017 Sep;28(9):2812-2823.

Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial. Beddhu S, Rocco MV, Toto R, Craven TE, Greene T, Bhatt U, Cheung AK, Cohen D, Freedman BI, Hawfield AT, et al., SPRINT Research Group. Ann Intern Med. 2017 Sep;167(6):375-383.

Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, Cheung AK, Cleveland ML, Coker LH, Crowe MG, et al., JAMA. 2019 Feb;321(6):553-561.

Intensive vs standard blood pressure control in adults 80 years or older: a secondary analysis of the Systolic Blood Pressure Intervention Trial. Pajewski NM, Berlowitz DR, Bress AP, Callahan KE, Cheung AK, Fine LJ, Gaussoin SA, Johnson KC, King J, Kitzman DW, et al., J Am Geriatr Soc. 2019 Mar;68(3):496-504.

Association of intensive vs standard blood pressure control with cerebral white matter lesions. SPRINT MIND Investigators for the SPRINT Research Group, Nasrallah IM, Pajewski NM, Auchus AP, Chelune G, Cheung AK, Cleveland ML, Coker LH, Crowe MG, Cushman WC, Cutler JA, et al., JAMA. 2019 Aug;322(6):524-534.

Final Report of a Trial of Intensive versus Standard Blood-Pressure Control. SPRINT Research Group, Lewis CE, Fine LJ, Beddhu S, Cheung AK, Cushman WC, Cutler JA, Evans GW, Johnson KC, Kitzman DW, et al., N Engl J Med. 2021 May 20;384(20):1921-1930.

U of U Health Key Faculty Collaborators

Srinivasan Beddhu, MD
Adam Bress, PharmD
Gordon Chelune, PhD
Mark A. Supiano, MD
Tom Greene, PhD

Blood Pressure Treatment Target | PI: Alfred Cheung, MD

November 1, 2015May 26, 2021

Host-Microbe Battles Over Iron

Hosts and pathogens are locked in an endless battle to gain selective advantages over one another. Host-pathogen interactions, therefore, provide valuable systems for studying evolutionary genetics, natural selection, microbiology, and infectious disease. The sequestration of essential iron has emerged as a crucial innate defense system termed nutritional immunity, leading pathogens to evolve mechanisms of ‘iron piracy’ to scavenge this essential metal from host proteins. This battle for iron carries numerous consequences not only for host-pathogen evolution but also for microbial community interactions.

The Elde lab demonstrated that the iron carrier protein transferrin has evolved to allow hosts to escape bacterial “iron piracy”. For example, one transferrin polymorphism allows hosts to evade iron piracy by the pathogenic bacterium, Haemophilus influenzae, revealing a functional basis for standing genetic variation in the human population. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens.

References:

Escape from bacterial iron piracy through rapid evolution of transferrin.
Barber MF, Elde NC. Science. 2014 Dec;346(6215):1362.

Buried treasure: Evolutionary perspectives on microbial iron piracy.
Barber MF, Elde NC. Trends Genet. 2015 Nov;31(11):627.

Press Releases and Media:

University of Utah Health: “Human DNA Shows Traces of 40 Million-Year Battle for Survival Between Primate and Pathogen”

New York Times
National Geographic

Host-Microbe Battles Over Iron | PI: Nels C. Elde, PhD

September 1, 2015June 28, 2021

Age-Related Sarcopenia and Recovery Following Muscle Disuse

Aging coincides with frequent periods of muscle disuse and, when combined with subsequent poor muscle recovery, contributes to sarcopenia, loss of muscle during aging. In order to develop effective interventions to offset deficits in muscle mass and function, Micah Drummond, PhD, and colleagues studied the cellular and molecular events that accompany muscle disuse in older adults. They found that older adults are more susceptible to losing muscle mass and strength during disuse than young persons because of reduced protein synthesis and increased protein breakdown in the muscle. To intervene during disuse periods, they implemented therapeutic tools (e.g. protein supplementation and neuromuscular electrical stimulation) that increase protein synthesis and moderate muscle breakdown. Although weakness persisted, this dual treatment was successful in maintaining muscle mass. Their research suggests that current countermeasures will need to be refined, and new pharmacological agents explored, to maintain full muscle functionality during muscle disuse in older people.

References:

Age-related differences in leg lean mass, protein synthesis and skeletal muscle markers of proteolysis after bed rest and exercise rehabilitation. Tanner, R.E., L. Brunker, J. Agergaard, K. Barrows, R. Briggs, O. Kwon, L. Young, P. Hopkins, E. Volpi, R. Marcus, P. LaStayo, M.J. Drummond. Journal of Physiology. 2015 September 15;593(18): 4259.

Neuromuscular electrical stimulation combined with protein ingestion preserves thigh muscle mass but not muscle function in healthy older adults during 5-days of bed rest. Reidy PT, McKenzie AI, Brunker P, Nelson DS, Barrows KM, Supiano M, LaStayo PC, Drummond, MJ. Rejuvenation Research. 2017 December;20(6):449.

Age-dependent skeletal muscle transcriptome response to bed rest-induced atrophy. Mahmassani ZS, Reidy PT, McKenzie AI, Stubben C, Howard MT, Drummond MJ. Journal of Applied Physiology. 2019 April 1;126(4):894.

Age-Related Sarcopenia and Recovery Following Muscle Disuse | PI: Micah J. Drummond, PhD

August 18, 2015June 28, 2021

Genetic Risk for Polycystic Ovary Syndrome

Fifteen gene regions that significantly increase risk for polycystic ovary syndrome (PCOS) are shown by red dots that lie above the green line, indicating high statistical significance.

Polycystic ovary syndrome (PCOS) is characterized by excessive androgen hormone, irregular menstrual cycles, and polycystic ovaries on ultrasound. Affected women also frequently experience metabolic disturbances, including obesity, and face increased risk for type 2 diabetes. University of Utah Health investigator Corrine Welt, MD, and collaborators performed an international meta-analysis of whole genome association studies combining over 10 million genetic markers in more than 10,000 European women with PCOS and 100,000 controls.

They found three new risk variants associated with PCOS. The data demonstrate that the genetic architecture does not differ based on the diagnostic criteria used for PCOS. They also demonstrate a genetic pathway in PCOS that is shared with male pattern baldness, representing the first evidence for shared disease biology for PCOS in men. The data also demonstrate a novel genetic pathway associated with depression, demonstrating linked genetic risk for PCOS and depression. It also demonstrated that the genetic architecture underlying PCOS remains the same regardless of which criteria are used for diagnosis.

These discoveries provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential, and mental health. The data will help physicians better target underlying risk factors and comorbid disease in women with PCOS.

References:

Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume. Saxena R, Bjonnes AC, Georgopoulos NA, Koika V, Panidis D, Welt CK. Hum Reprod. 2015 Jul;30(7):1697-1703.

Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, Karaderi T, Barber TM, McCarthy MI, Franks S, Lindgren CM, Welt CK, Diamanti-Kandarakis E, Panidis D, Goodarzi MO, Azziz R, Zhang Y, James RG, Olivier M, Kissebah AH; Reproductive Medicine Network, Stener-Victorin E, Legro RS, Dunaif A. Nat Commun. 2015 Aug 18;6:7502.

Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, Bjonnes A, Broer L, Dunger DB, Halldorsson BV, Lawlor DA, Laval G, Mathieson I, McCardle WL, Louwers Y, Meun C, Ring S, Scott RA, Sulem P, Uitterlinden AG, Wareham NJ, Thorsteinsdottir U, Welt C, Stefansson K, Laven JSE, Ong KK, Perry JRB. Nat Commun. 2015 Sep 29;6:8464.

Press Releases and Media:

University of Utah Health: Researchers Identify Genes Associated with Polycystic Ovary Syndrome; New Hope for Women With PCOS

GenomeWeb
Medical XPress
AJMC

Genetic Risk for Polycystic Ovary Syndrome | PI: Corrine K. Welt, MD

July 1, 2015June 11, 2021

Genetics of Alcohol Abuse – from Flies to Humans

Genetic factors play a major role in the development of human alcohol use disorder. The fruit fly, Drosophila melanogaster, has been used as a model organism to isolate and characterize genes in many physiological disorders. Like many humans, flies initially dislike alcohol, but develop a taste for it with continued experience. In an unbiased screen, the lab directed by Adrian Rothenfluh, PhD, isolated flies lacking a certain gene (Rsu1) that produces a strong liking for alcohol, even before repeated exposure. Their investigations in Drosophila showed that Rsu1 and downstream signaling molecules regulate actin dynamics; genetic manipulations that increase actin filament turnover lead to accelerated development of alcohol preference, while manipulations that increase actin filament stability abolish the development of preference. Furthermore, they showed that variants of the human Rsu1 gene are associated with altered drinking behavior and with changes in brain activity after receiving a reward. Together, these findings show the power of unbiased approaches in model organisms to generate insights that can be translated to humans to advance scientific understanding of the genetic mechanisms driving alcohol use disorder.

References:

Rsu1 regulates ethanol consumption in drosophila and humans. Ojelade SA, Jia T, Rodan AR, Chenyang T, Kadrmas JL, Cattrell A, Ruggeri B, Charoen P, Lemaitre H, Banaschewski T, Büchel C, Bokde ALW, Carvalho F, Conrod F, Flor H, Frouin V, Gallinat J, Garavan H, Gowland PA, Heinz A, Ittermann B, Lathrop M, Lubbe S, Martinot JL, Paus T, Smolka MN, Spanagel R, O’Reilly PF, Laitinen J, Veijola JM, Feng J, Desrivières S, Jarvelin MR, Schumann G, Rothenfluh A. Proc. Natl. Acad. Sci. U.S.A. 2015 Jul;112(30):E4085

Altered actin filament dynamics in the drosophila mushroom bodies lead to fast acquisition of alcohol consumption preference. Butts AR, Ojelade SA, Pronovost ED, Seguin A, Merrill CB, Rodan AR, Rothenfluh A. J Neurosci. 2019 Nov 6;39(45):8877.

Press Releases and Media:

Irish Times
PNAS

U of U Health Key Faculty Collaborators

Aylin Rodan, PhD, MD
Julie Kadrmas, PhD
Mary Beckerle, PhD

Genetics of Alcohol Abuse – from Flies to Humans | PI: Adrian Rothenfluh, PhD

June 20, 2015June 28, 2021

The Role of IDH Mutation in Human Brain Tumors

Recent studies have identified mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) in gliomas, human brain tumors that are currently incurable. Sheri Holmen, PhD, was the first to show that IDH mutations, on the appropriate genetic background, resulted in glioma initiation and growth. This discovery provided the basis of a pre-clinical model for testing the contribution of other molecular alterations to the pathogenesis of, and the effects of various treatments on, these tumors. Howard Colman, MD, PhD, and colleagues subsequently demonstrated that increased DNA alterations were associated with higher-grade gliomas and worse prognoses. Using the Utah Population Database, they confirmed that a particular DNA germline variant was associated with elevated risk of developing oligodendrogliomas, a subtype of IDH-mutant tumors. They also found that this allele was associated with increased risk of other cancers. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) considered elements of this work when drafting recommended revisions to the World Health Organization’s guidelines around diagnosing and grading IDH-mutant gliomas.

References:

IDH1 and IDH2 mutations in gliomas. Cohen AL, Holmen SL, Colman H. Current Neurology and Neuroscience Reports. 2013 May 1, 2013;13(5):345. https://doi.org/10.1007/s11910-013-0345-4.

DNA copy number analysis of grade ii-iii and grade iv gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status. Cohen A, Sato M, Aldape K, Mason CC, Alfaro-Munoz K, Heathcock L, South ST, Abegglen LM, Schiffman JD, Colman H. Acta Neuropathologica Communications. 2015 June 20;3:34. https://doi.org/10.1186/s40478-015-0213-3.

Mutant idh1 promotes glioma formation in vivo. Philip, Beatrice, Yu DX, Silvis MR, Shin CH, Robinson JP, Robinson GL, Welker AE, et al. Cell Reports. 2018 May 1;23(5):1553. https://doi.org/10.1016/j.celrep.2018.03.133.

cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Brat DJ, Aldape K, Colman H, Figrarella-Branger D, Fuller GN, Giannini C, Holland EC, et al. Acta Neuropathologica. 2020 March;139(3):603. https://doi.org/10.1007/s00401-020-02127-9.

The Role of IDH Mutation in Human Brain Tumors | PI: Howard Colman, MD, PhD, Adam L. Cohen, MD & Sheri L. Holmen, PhD