Discoveries – Page 4 – Discovery and Innovation at University of Utah Health

August 1, 2018June 28, 2021

Elective Labor Induction in First-Time Moms at 39 Weeks of Gestation

The optimal timing of delivery for low-risk pregnancies is not known. Risks of complications increase after 39 weeks of gestation, but inducing labor may increase the need for cesarean delivery, leading to policies prohibiting elective induction before 41 weeks. To address this dilemma, Robert Silver, MD, and colleagues at the University of Utah Department of Obstetrics & Gynecology randomized 6,106 low-risk, first-time pregnant women to either induction of labor at 39 weeks or expectant management (waiting for spontaneous labor but undergoing active intervention should the need arise). Results of the study showed that the induced group had a 16% lower rate of cesarean deliveries, lower rates of some medical complications, higher satisfaction with their labor experience, and similar or lower medical costs.

These findings led to a general acceptance of elective induction of labor as a reasonable option for first-time mothers at 39 weeks’ gestation. Further research has facilitated personalized calculations of probability of vaginal birth after induction and risk of medical complications with expectant management, empowering women to make informed decisions about their birth experience.

References:

Labor induction versus expectant management for low-risk nulliparous women. Grobman WA, Rice MM, Reddy UM, Tita ATN, Silver RM, Mallett G, Hill K, Thom EA, El-Sayed YY, Perez-Delboy A, Rouse DJ, Saade GR, Boggess KA, Chauhan SP, Iams JD, Chien EK, Casey BM, Gibbs RS, Srinivas SK, Swamy GK, Simhan HN, Macones GA. New Engl J Med. 2018 Aug;379(6):513-523.

Cost of elective labor induction compared with expectant management in nulliparous women. Einerson BD, Nelson RE, Sandoval G, Esplin MS, Branch DW, Metz TD, Silver RM, Grobman WA, Reddy UM, Varner M, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) maternal-Fetal Medicine Units (MFMU) Network. Obstet Gynecol. 2020 Jul;136(1):19-25.

Customized probability of vaginal delivery with induction of labor and expectant management in nulliparous women at 39 weeks of gestation. Silver RM, Rice MM, Grobman WA, Reddy UM, Tita ATN, Mallett G, Hill K, Thom EA, El Sayed YY, Wapner RJ, Rouse DJ, Saade GR, Thorp JM Jr, Chauhan SP, Chien EK, Casey BM, Gibbs RS, Srinivas SK, Swamy GK, Simhan HN, Macones GA; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units (MFMU) Network. Obstet Gynecol. 2020 Oct;136(4):698-705.

U of U Health Key Faculty Collaborators

Torri D. Metz, MD
Michael W. Varner, MD
Brett Einerson, MD
M. Sean Esplin, MD

Elective Labor Induction in First-Time Moms at 39 Weeks of Gestation | PI: Robert M. Silver, MD

July 5, 2018June 28, 2021

Chronic Hypoxia Exposure Worsens Depression

University of Utah Health investigator Perry Renshaw, MD, PhD, and colleagues combine epidemiology, animal models, and human neuroimaging to study how impaired brain bioenergetics affect psychiatric disorders. They first reported a link between altitude and suicide in the U.S., a finding since replicated in three other continents. People living at high altitude are exposed to hypobaric hypoxia, and the partial pressure of oxygen in arterial blood is reduced in people at 4,500ft (Salt Lake City, UT) compared to sea level. Both Hypobaric hypoxia and chronic hypoxic conditions such as pulmonary, cardiovascular, and sleep disorders and smoking are linked to depression. Preclinical studies found that hypobaric hypoxia disrupts brain serotonin and bioenergetic systems, with women being particularly vulnerable.

Using magnetic resonance imaging, researchers also found that, compared to sea level, humans at 4,500 feet exhibit deficits in creatine, a high energy neurometabolite. The Renshaw Lab subsequently conducted animal and human studies and observed that targeted creatine supplementation improved brain bioenergetics and reduced depressive symptoms. Future goals aim to define the mechanisms by which hypobaric hypoxia promotes depression and suicide risk, and to test new treatment strategies.

References:

Altitude, gun ownership, rural areas, and suicide. Kim, N, Mickelson JB, Brenner BE, Haws CA, Yurgelun-Todd DA, Renshaw PF. Am J Psychiatry. 2011 Jan;168(1):49.

Incidence of major depressive episode correlates with elevation of substate region of residence. DelMastro, K, Hellem T, Kim N, Kondo D, Sung YH, Renshaw PF. J Affect Disord. 2011 Mar;129(1):376.

Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. Kondo DG, Sung YH, Hellem TL, Fiedler KK, Shi X, Jeong EK, Renshaw PF. J Affect Disord. 2011 December;135(1):354.

Hypobaric hypoxia induces depression-like behavior in female, Sprague-Dawley rats, but not in males. Kanekar S., Bogdanova OV, Olson PR, Sung YH, D’Anci KE, Renshaw PF. High Alt Med Biol. 2015 Mar;16(1):52.

Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Kondo DG, Forrest LN, Shi X, Sung YH, Hellem TL, Huber RS, Renshaw PF. Amino Acids. 2016 August;48(8):1941.

Increased anxiety and anhedonia in female rats following exposure to altitude. Sheth C, Ombach H, Olson P, Renshaw PF, Kanekar S. High Alt Med Biol. 2018 Mar;19(1):81.

Hypobaric hypoxia exposure in rats differentially alters antidepressant efficacy of the selective serotonin reuptake inhibitors fluoxetine, paroxetine, escitalopram and sertraline. Kanekar S., Sheth CS, Ombach HJ, Olson PR, Bogdanova OV, Petersen M, Renshaw CE, Sung YH, D’Anci KE, Renshaw PF. Pharmacol Biochem Behav. 2018 July;170:25.

Press Releases and Media

University of Utah Health: “Higher Altitudes Hide Deadly Problem: Increased Risk for Suicide” (2010); “Study Links Thin Air, Higher Altitudes to Depression in Female Rats” (2015); “Common Antidepressents Are Less Effective at High Altitudes, Rodent Study Suggests” (2018)

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U of U Health Key Faculty Collaborators

Deborah Yurgelun Todd, PhD
Brent M. Kious, MD, PhD
Young-Hoon Soon, MD
Xianfeng Shi, PhD

Chronic Hypoxia Exposure Worsens Depression | PI: Perry F. Renshaw, MD, PhD, Shami Kanekar, PhD & Douglas G. Kondo, MD

July 1, 2018June 28, 2021

A Genetic Mechanism Contributing to Racial Differences in Vascular Disease

A Genetic Mechanism Graphic- Contributing to Racial Differences in Vascular Disease

Heart attacks and strokes result from clots formed in the blood vessels of the heart or brain, respectively. The laboratory of Paul Bray, MD, demonstrated that platelets from Black individuals were more reactive than those from White individuals, suggesting a genetic basis for some of the racial discrepancy observed in vascular diseases associated with clotting. Having observed these differences, his team went on to identify the genetic variant responsible for this hyper-reactivity, common in people of African, but not European, ancestry. By analyzing DNA from roughly 13,000 patients with heart attacks and strokes, they showed the hyper-reactive gene variant was associated with increased risks for stroke and reduced bleeding. Anti-platelet drugs are the first-line pharmacotherapy for these vascular diseases. However, additional work by Bray’s group showed that the commonly used drug, the P2Y12 inhibitor clopidogrel, did not inhibit platelet hyper-reactivity among individuals with the genetic variant (primarily Blacks), whereas another P2Y12 inhibitor, ticagrelor, effectively inhibited platelet reactivity in both Blacks and Whites. These discoveries have laid the groundwork for individualized anti-platelet therapies in disorders with racial predilections.

References:

Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Edelstein LC, Simon LM, Montoya RT, Holinstat M, Chen ES, Bergeron A, Kong X, Nagalla S, Mohandas N, Cohen DE, Dong J-f, Shaw C, Bray PF. Nat Med. 2013 December;19(12):1609.

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Edelstein LC, Simon LM, Lindsay CR, Kong X, Montoya RT, Tourdot BE, Chen ES, Ma L, Coughlin S, Nieman M, Holinstat M, Shaw CA, Bray PF. Blood. 2014 November 27;124(23):3450.

Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis. Tourdot BE, Conaway S, Niisuke K, Edelstein LC, Bray PF, Holinstat M. Arterioscler Thromb Vasc Biol. 2014 December;34(12):2644.

A function-blocking PAR4 antibody is markedly antithrombotic in the face of a hyperreactive PAR4 variant. French SL, Thalmann C, Bray PF, Macdonald LE, J Murphy AJ, Sleeman MW, Hamilton JR. Blood Adv. 2018 June 12;2(11):1283.

Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics. Tourdot BE, Stoveken H, Trumbo D, Yeung J, Kanthi Y, Edelstein LC, Bray PF, Tall G, Holinstat M. Arterioscler Thromb Vasc Biol. 2018 July;38(7):1632.

Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial. Tricoci P, Neely M, Whitley M, Edelstein LC, Simon LM, Shaw C, Fortina P, Moliterno DJ, Armstrong PW, Aylward P, White H, Van de Werf F, Jennings LK, Wallentin L, Held C, Harrington RA, Mahaffey KW, Bray PF. Blood Cells, Molec and Dis. 2018 September;72:37.

The protease-activated receptor 4 Ala120Thr variant alters platelet responsiveness to low-dose thrombin and protease-activated receptor 4 desensitization, and is blocked by non-competitive P2Y₁₂ inhibition. Whitley MJ, Henke DM, Ghazi A, Nieman M, Stoller M, Simon LM, Chen E, Vesci J, Holinstat M, McKenzie SE, Shaw CA, Edelstein LC, Bray PF. J Thromb Haemost. 2018 December;16(12):2501.

A Genetic Mechanism Contributing to Racial Differences in Vascular Disease | PI: Paul F. Bray, MD

June 13, 2018May 26, 2021

Structure and Function of the Polycystic Kidney Disease Channel

Structure of Polycystic Kidney Disease 2 Channel in a membrane.

The kidney senses and responds to physiological changes, such as pH, ionic strength, pressure, and nutrient levels. Sensing is mediated by a coupled sensor/ion channel complex called the Polycystic Kidney Disease Channel, which is composed of two subunits, the PKD1 (the primary sensor) and PKD2 (the channel). Autosomal dominant PKD mutations are amongst the most common monogenic disorders and lead to untreatable end-stage renal failure.

To learn how this system works and is adversely affected by PKD mutations, Cao, Shen, and colleagues determined a high-resolution cryo-EM structure of the PKD2 channel in lipid nanodiscs. This breakthrough accomplishment provided considerable insight into how the PKD2 channel functions. The result was also the first time that cryo-EM was used to determine a high-resolution membrane protein structure at the University of Utah. Finally, it was one of the first membrane protein structures determined within a native-like lipid nanodisc environment, a technology that Cao helped to pioneer.

References:

TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Gao Y, Cao E, Julius D, Cheng Y. Nature. 2016 Jun;534(7607):347.

The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D, Clapham DE, Cao E. Cell. 2016 Oct;167(3):763.

Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels. Zheng W, Yang X, Hu R, Cai R, Hofmann L, Wang Z, Hu Q, Liu X, Bulkley D, Yu Y, Tang J, Flockerzi V, Cao Y, Cao E, Chen XZ. Nature Communications. 2018 Jun;9(1):2302.

Press Releases and Media:

University of Utah Health: “Unmasking a “Silent Killer”: A Culprit Behind Polycystic Kidney Disease”

Structure and Function of the Polycystic Kidney Disease Channel | PI: Erhu Cao, PhD & Peter Shen, PhD

April 1, 2018July 1, 2021

HER Salt Lake City Contraceptive Initiative and Family Planning Elevated

The U.S. Healthy People 2020 initiative aims to improve pregnancy planning and increase access to the full range of contraceptive methods. Utah presents unique barriers to contraceptive services, including limited public funding and geographical regions with limited family planning services. The University of Utah Health Division of Family Planning, in partnership with Planned Parenthood of Utah, conducted a prospective cohort study (HER Salt Lake) that provided 7,402 individuals in Salt Lake County with same-day, no-cost contraception and the ability to change or discontinue their contraceptive method without cost over three years.

Led by U of U Health investigator David Turok, MD, the study found that removing cost barriers resulted in a significant shift to more effective contraceptive methods, including intrauterine devices and other implantable devices. This work formed the foundation for a statewide contraceptive initiative called Family Planning Elevated which has already provided no-cost contraception to 13,000 people at 28 participating clinics. Findings from HER Salt Lake and Family Planning Elevated will continue to inform future clinical care, policies, and translational research.

References:

Contraceptive method use during the community-wide HER Salt Lake Contraceptive Initiative. Sanders JN, Myers K, Gawron LM, Simmons RG, Turok DK. Am J Public Health. 2018 Apr;108(4):550-556.

Evaluating a longitudinal cohort of clinics engaging in the Family Planning Elevated Contraceptive Access Program (FPE CAP): study protocol of a comparative interrupted time series analysis. Simmons R, Myers K, Gero A, Sanders JN, Quade C, Mulholland M, Turok DK. JMIR Res Protoc. 2020 Oct 16;9(10):e18308.

Press Releases and Media:

University of Utah Health: “With Cost Removed, Women Choose More Effective Contraceptive Methods“; “University of Utah Health Announces Family Planning Elevated, A Statewide Contraceptive Initiative”

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HER Salt Lake

U of U Health Key Faculty Collaborators

Jessica Sanders, PhD
Rebecca Simmons, PhD
Kyl Myers, PhD

HER Salt Lake City Contraceptive Initiative and Family Planning Elevated | PI: David Turok, MD

February 22, 2018May 26, 2021

Mechanisms of Epigenetic Inheritance

Placeholder nucleosomes program DNA hypomethylation.

A central issue in epigenetics is whether and how epigenetic information in gametes (sperm and egg) is inherited. Cairns and colleagues discovered that “Placeholder” nucleosomes, containing histone variants, occupy DNA regions lacking methylation in both sperm and early embryos. Placeholder nucleosomes establish regions of the genome that lack DNA methylation, and their depletion leads to DNA methylation of promoters and enhancers, and transcriptional silencing.

Placeholder nucleosomes reside at promoters of housekeeping genes and early embryonic transcription factors. Housekeeping genes with Placeholder become active when genome-wide transcription is activated, whereas developmental genes with Placeholder become ‘poised’ by receiving two additional chromatin modifications, which are targeted by particular transcription factors. Taken together, the results defined a chromatin entity – Placeholder nucleosomes – that are inherited from the germline and remain at promoters and enhancers in embryos, where they help define both active and ‘poised’ genes in the embryo.

References:

Placeholder nucleosomes underlie germline-to-embryo DNA methylation reprogramming. Murphy PJ, Wu SF, James CR, Wike CL, Cairns BR. Cell. 2018 Feb;172(5):993.

Press Releases and Media:

University of Utah Health: Working in Harmony: New Insights into How Packages of DNA Orchestrate Development

Mechanisms of Epigenetic Inheritance | PI: Bradley R. Cairns, PhD

February 7, 2018May 26, 2021

Vascular Inflammation in Malaria Pathogenesis

Targeting EphA2 prevents breakdown of the blood brain barrier in cerebral malaria. Plasmodium-infected mice were injected with EphA2 days 5-7 post-infection and vascular leakage monitored by leakage of Evans blue dye. The amount of dye that has entered the cerebral tissue was extracted and quantified (right panel).

The pathogenesis of malaria is characterized by vascular inflammation exacerbated by immune cells that travel to areas where red blood cells infected with parasites stick to the endothelium lining the blood vessels. The molecules that mediate this process are not well-understood, yet such knowledge may lead to therapeutic targets that block vascular inflammation due to malaria.

The Lamb lab has made significant discoveries demonstrating a key role for receptor tyrosine kinase family Eph receptors in malaria pathogenesis. They have identified EphB2 as a critical mediator of malaria-induced liver fibrosis and EphA2 as a molecule essential for the integrity of the blood-brain barrier in cerebral malaria. The malaria studies were carried out as part of the Utah Global Health Initiative with the Pasteur Institute in Cameroon, Central Africa.

Tracey Lamb, Ph.D. with Lawrence Ayong, Ph.D. and team at Centre Pasteur du Cameroun in Yaoundeé, Cameroon.

References:

The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Mimche PN, Brady LM, Bray CF, Lee CM, Thapa M, King TP, Quicke K, McDermott CD, Mimche SM, Grakoui A, Morgan ET, Lamb TJ. Hepatology. 2015 Sep;62(3):900.

EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis in mice via activation of hepatic stellate cells. Mimche PN, Lee CM, Mimche SM, Thapa M, Grakoui A, Henkemeyer M, Lamb TJ. Sci Rep. 2018 Feb;8(1):2532.

Press Releases and Media:

University of Utah Health: “Discovery Paves Path Forward in the Fight Against the Deadliest Form of Malaria”

Vascular Inflammation in Malaria Pathogenesis | PI: Tracey J. Lamb, PhD

January 29, 2018May 26, 2021

Animation of the HIV Life Cycle

Atomically accurate molecular animations provide a unique opportunity for generating and testing new mechanistic hypotheses and promoting scientific communication and public outreach. Iwasa is a leader in the creation of sophisticated, dynamic 3D visualizations of biological processes. In 2018, she completed and released a molecular animation of the entire HIV life cycle (http://scienceofHIV.org), which was featured at the International Conference on Retroviral and Opportunistic Infections (CROI March 2018).

Our NIH P50 CHEETAH Center sponsors this work and as additional data become available, the animation website will be updated to include additional animations that illustrate how antiretroviral therapies work, how a cure might be achieved, how innate immune restriction factors block HIV replication, and the history of HIV research and treatment in Utah.

Press Releases and Media:

University of Utah Health: “Can Scientific Animations Lead to New Discoveries? Janet Iwasa, Ph.D., Says Next-Generation Visualization Speeds Research”

TED
Scientific American Magazine
Science Magazine
The NIH Director’s blog
CNET
PBS NOVA
Projected at a large scale in the 2019 Illuminate Salt Lake City Festival

Animation of the HIV Life Cycle | PI: Janet Iwasa, PhD

January 19, 2018December 17, 2021

Identifying RNAs from Invading Viruses

Dicer discriminates dsRNA with overhanging termini (self) from viral dsRNA (non-self).

Organisms must regulate gene expression and also distinguish their RNA molecules (self) from the RNAs of invading viruses (non-self). Biochemical and structural studies from Bass, Shen, Iwasa, and colleagues revealed how Dicer-2, an RNA processing, and antiviral defense enzyme, distinguishes and differentially processes double-stranded RNA (dsRNA) substrates by sensing the unique chemistry at their termini. The study also revealed that human Dicer evolved with distinct activities from invertebrate Dicers, and this discovery is paving the way for altering the antiviral defense for therapeutic benefits.

References:

Dicer uses distinct modules for recognizing dsRNA termini. Sinha NK, Iwasa J, Shen PS, Bass BL. Science. 2018 Jan;359(6373):329.

Press Releases and Media:

University of Utah Health: “Meet the Tiny Machine in Cells that Massacres Viruses”

ScienceDaily
Genetic Engineering and Biotechnology News

Identifying RNAs from Invading Viruses | PI: Brenda L. Bass, PhD, Peter Shen, PhD & Janet Iwasa, PhD

January 11, 2018May 26, 2021

Intercellular Communication in Long Term Memory

Arc forms virus-like capsids via a conserved retroviral Gag capsid domain. (A) EM images of purified Arc protein. Insets show Arc capsids. (B) Arc mRNA is locally translated in dendrites, and Arc protein forms capsids which encapsulate RNAs and proteins that are released, mediating transfer to neighboring cells.

How can cells in the brain retain information for years, even though most proteins turn over in minutes to days? The neuronal gene Arc is critical for transducing experience and learning into long-lasting changes in the brain.

Shepherd and colleagues found that the Arc gene is derived from a family of retrotransposons, and that the Arc protein can self-assemble into virus-like capsids that are released from neurons in membrane-enclosed vesicles that transfer RNA and proteins cell-to-cell. These findings open a new area of investigation in the cell biology of cell-to-cell communication and mechanisms of brain plasticity by uncovering a novel intercellular communication pathway that resembles retrovirus biology.

Jason Shepherd, PhD. and Elissa Pastuzyn, Ph.D.

References

The neuronal gene Arc encodes a repurposed retrotransposon Gag protein that mediates intercellular RNA transfer. Pastuzyn ED, Day CE, Kearns RB, Kyrke-Smith M, Taibi AV, McCormick J, Yoder N, Belnap DM, Erlendsson S, Morado DR, Briggs JAG, Feschotte C, Shepherd JD. Cell. 2018 Jan;172(1-2):275.

Press Releases and Media:

University of Utah Health: “Surprise: A Virus-Like Protein is Important for Cognition and Memory”

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Intercellular Communication in Long Term Memory | PI: Jason Shepherd, PhD

December 5, 2017January 25, 2023

Neural and Cardiac Responses to Hypoglycemia

In the setting of insulin therapy, patients with Type 1 diabetes (T1D) are at particularly high risk for hypoglycemia (low blood sugar) because of an impaired ability of the brain to sense and respond appropriately to hypoglycemia. The physiologic basis of this impairment is, however, unclear. The laboratories of Simon Fisher, MD, Owen Chan, PhD, and Candace Reno, PhD, demonstrated that brain glucose sensing was impaired in rats with recurrent hypoglycemia as a result of defective glucose and lactate metabolism within the neurons and astrocytes in the hypothalamus. The resultant abnormal release of neurotransmitters—such as GABA, glutamate and dopamine—led to inadequate activation of hormonal responses to hypoglycemia. This detrimental effect, however, could be prevented by treatment with the beta-blocker carvedilol in rats. They further demonstrated that severe hypoglycemia led to coma, brain damage and fatal cardiac arrhythmias, and these effects were mediated by excessive activation of the autonomic nervous system. Based on these results, the investigators have launched a clinical trial to examine the efficacy of the drug metoclopramide to restore the neurotransmitter and hormonal responses and awareness to hypoglycemia in people with T1D.

References:

Brain glut4 knockout mice have impaired glucose tolerance, decreased insulin sensitivity, and impaired hypoglycemic counterregulation. Reno CM, Puente EC, Sheng Z, Daphna-Iken D, Bree AJ, Routh VH, Kahn BB, Fisher SJ. Diabetes. 2017 March;66(3):587. https://doi.org/10.2337/db16-0917

Impaired glutamatergic neurotransmission in the ventromedial hypothalamus may contribute to defective counterregulation in recurrently hypoglycemic rats. Chowdhury GMI, Wang P, Ciardi A, Mamillapalli R, Johnson J, Zhu W, Eid T, Behar, Chan O. Diabetes. 2017 July;66(7):1979. https://doi.org/10.2337/db16-1589

Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia. Reno CM, VanderWeele J, Bayles J, Litvin M, Skinner A, Jordan A, Daphna-Iken D, Fisher S. Diabetes. 2017 December;66(12):3091. https://doi.org/10.2337/db17-0306

Prevention of severe hypoglycemia-induced brain damage and cognitive impairment with verapamil. Jackson DA, Michael T, Vieira de Abreu A, Agarwal R, Bortolato M, Fisher SJ. Diabetes. 2018 October;67(10):2107. https://doi.org/10.2337/db18-0008

Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in sprague-dawley rats. Farhat R, Su G, Sejling AS, Knight N, Fisher SJ, Chan O. Diabetologia. 2019 April;62(4):676. https://doi.org/10.1002/edm2.226

Severe hypoglycemia-induced fatal cardiac arrhythmias are mediated by the parasympathetic nervous system in rats. Reno CM, Bayles J, Huang Y, Oxspring M, Hirahara AM, Dosdall DJ, Fisher SJ. Diabetes. 2019 November;68(11):2107. http://doi.org/10.2337/db19-0306

U of U Health Key Faculty Collaborators:

Derek J. Dosdall, PhD
Marco Bortolato, MD, PhD

Neural and Cardiac Responses to Hypoglycemia | PI: Simon J. Fisher, MD, PhD, Owen Chan, PhD & Candace M. Reno, PhD

December 1, 2017June 28, 2021

ARF6 Plays Key Role in Diabetes-Induced Blindness

Diabetic macular edema, the most common cause of blindness in the United States, is triggered by inflammation, the growth of new blood vessels, and fluid leakage from blood vessels into the retina. Vascular endothelial growth factor (VEGF) is a protein known to play a major role in all of those processes. However, existing anti-VEGF treatments often fail to achieve adequate effects.

University of Utah Health researcher Weiquan Zhu, PhD, and colleagues identified a protein, known as ARF6, which regulates the effects of VEGF by maintaining and amplifying its receptor signaling, thus stimulating a series of cascading responses that lead to diabetic retinal edema. In mouse and rat studies, when ARF6 was eliminated through genetic manipulation in blood-vessel endothelial cells or suppressed through injection of an inhibitory compound, NAV-2729, the eye was protected from fluid leakage and damage.

These results have important implications not only for the treatment of diabetic macular edema and other related eye diseases, but also for other disorders that involve VEGF receptor activation, such as acute and chronic inflammation and cancer.

References:

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy. Zhu W, Shi DS, Winter JM, Rich BE, Tong Z, Sorensen LK, Zhao H, Huang Y, Tai Z, Mleynek TM, Yoo JH, Dunn C, Ling J, Bergquist JA, Richards JR, Jiang A, Lesniewski LA, Hartnett ME, Ward DM, Mueller AL, Ostanin K, Thomas KR, Odelberg SJ, Li DY. J Clin Invest. 2017 Dec 1;127(12):4569-4582.

Press Releases and Media:

University of Utah Health: “Researchers identify protein that plays key role in diabetic blindness”

ScienceDaily
Diabetes Health Page
Medical News Today

U of U Health Key Faculty Collaborators

Mary Elizabeth Hartnett, MD, PhD
Diane M Ward, PhD
Lisa A. Lesniewski, PhD

ARF6 Plays Key Role in Diabetes-Induced Blindness | PI: Weiquan Zhu, PhD, Shannon J. Odelberg, PhD & Dean Y. Li, MD, PhD

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.

MedicalXpress
Scienceblog

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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UPR

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