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

May 1, 2019July 6, 2021

Combination Therapy for Treatment-Resistant Pancreatic Cancer

Kinsey and colleagues reported that inhibition of oncogenic KRAS→RAF→MEK→ERK signaling elicited autophagy, a process of cellular recycling that paradoxically protects pancreatic ductal carcinoma cells from the cytotoxic effects of KRAS pathway inhibition. Inhibition of MEK has been shown to activate the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Based on these observations, McMahon and colleagues reported that simultaneous combined inhibition of MEK plus autophagy displayed synergistic anti-proliferative effects against cultured pancreatic cancer cell lines and promoted regression of xenografted patient-derived pancreatic tumors in mice. Furthermore, xenografts of patient-derived NRAS-mutated melanoma or BRAF-mutated colorectal cancer displayed similarly enhanced responses. Finally, treatment of a pancreatic cancer patient with the combination of trametinib (MEK1/2 inhibitor) plus hydroxychloroquine (autophagy inhibitor) resulted in a partial, but nonetheless striking, disease response. The novelty is the discovery of the contingent dependence of RAS-, or BRAF-mutated tumors, including melanoma, colorectal and pancreatic cancer, on the autophagy pathway. This work suggests that this combination therapy represents a novel strategy to target RAS (oncoprotein)-driven cancers and has led to multiple ongoing clinical trials.

References:

MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival. Lee CS, Lee LC, Yuan TL, Chakka S, Fellmann C, Lowe SW, Caplen NJ, McCormick F, Luo J. Proc Natl Acad Sci USA. 2019 Mar 5;116(10):4508-4517.

Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, Gunda V, Pierobon M, Waters AM, George SD, Tomar G, Papke B, Hobbs GA, Yan L, Hayes TK, Diehl JN, Goode GD, Chaika NV, Wang Y, Zhang GF, Witkiewicz AK, Knudsen ES, Petricoin EF 3rd, Singh PK, Macdonald JM, Tran NL, Lyssiotis CA, Ying H, Kimmelman AC, Cox AD, Der CJ. Nat Med. 2019 Apr;25(4):628-640.

Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW 3rd, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M. Nat Med. 2019 May;25(5):861.

Press Releases and Media:

University of Utah Health: “Promising New Pancreatic Cancer Treatment Moves Forward”

Deseret News
Pancreatic Cancer Action Network
Science Daily
Health News Digest
AACR Publications
National Cancer Institute (NIH)

U of U Health Key Faculty Collaborators

Conan Kinsey, MD, PhD
Jill Shea, PhD
Jeffrey Yap, PhD
G. Weldon Gilcrease III, MD
Kajsa Affolter, MD
Alana Welm, PhD
Brian Welm, PhD
Courtney Scaife, MD
Eric Snyder, MD, PhD

Combination Therapy for Treatment-Resistant Pancreatic Cancer | PI: Martin McMahon, PhD

May 1, 2019May 26, 2021

Impact of Policy on VA Healthcare Utilization

Graph showing outpatient behavioral health visit numbers before and after Medicaid enrollment (n=7249), 2006-09.

Significant internal and external changes have affected the utilization of healthcare services in the Department of Veterans Affairs (VA). The VA is the largest integrated healthcare system in the U.S., with 9 million enrollees and 6 million users per year. Vanneman and colleagues have spearheaded research on the outcomes of increasing the portion of care currently outsourced to the private sector by the VA, as brought about by the Veterans Choice Act of 2014 and the MISSION Act of 2018.

The group has also worked to project the impacts of the Affordable Care Act for VA enrollees who newly gain Medicaid coverage. One notable finding is that total utilization of outpatient behavioral health services increases after veterans enroll in Medicaid – suggesting that Medicaid is best viewed as a complement rather than a substitute for VA outpatient behavioral health care.

References:

Iraq and Afghanistan veterans’ use of Veterans Health Administration and purchased care before and after Veterans Choice Program implementation. Vanneman ME, Harris AHS, Asch SM, Scott WJ, Murrell SS, Wagner TH. Med Care. 2017 Jul;55 Suppl 7 Suppl 1:S37.

The impact of medicaid enrollment on Veterans Health Administration enrollees’ behavioral health services use. Vanneman ME, Phibbs CS, Dally SK, Trivedi AN, Yoon J. Health Serv Res. 2018 Dec;53 Suppl 3:5238.

Differences in risk scores of veterans receiving community care purchased by the Veterans Health Administration. Rosen AK, Wagner TH, Pettey WBP, Shwartz M, Chen Q, Lo J, O’Brien WJ, Vanneman ME. Health Serv Res. 2018 Dec;53 Suppl 3:5438.

Recommendations for the evaluation of cross-system care coordination from the VA State-of-the-art Working Group on VA/Non-VA Care. Mattocks KM, Cunningham K, Elwy AR, Finley EP, Greenstone C, Mengeling MA, Pizer SD, Vanneman ME, Weiner M, Bastian LA. J Gen Intern Med. 2019 May;34(Suppl 1):18.

Impact of Policy on VA Healthcare Utilization | PI: Megan E. Vanneman, PhD

April 26, 2019May 26, 2021

Drug Discovery in Exotic Marine Symbionts

Comparative anatomy and life position of two different species of giant shipworms.

Rare and exotic marine organisms have proven to be a promising source of new drugs and other bioactive compounds. Haygood and collaborators have discovered that giant shipworms and other mollusks harbor a rich ecosystem of symbiotic bacteria, and that the symbiotic relationships between marine bacteria and marine animals are based on chemical signals exchanged between mollusks, for instance, and their bacterial symbionts.

The discoveries garnered significant attention owing to their potential for providing rich platforms for drug discovery. The “wooden-steps” hypothesis proposed that large chemosynthetic mussels found at deep-sea hydrothermal vents descend from much smaller species associated with sunken wood and other organic deposits and that the endosymbionts of these progenitors made use of hydrogen sulfide from biogenic sources (e.g., decaying wood) rather than from vent fluids. The study of bacterial symbiosis in exotic organisms, such as shipworm mollusks, illustrates universal principles that may be applied to the human microbiome.

References:

Discovery of chemoautotrophic symbiosis in the giant shipworm Kuphus polythalamia (Bivalvia: Teredinidae) extends wooden-steps theory. Distel DL, Altamia MA, Lin Z, Shipway JR, Han A, Forteza I, Antemano R, Limbaco MGJP, Tebo AG, Dechavez R, Albano J, Rosenberg G, Concepcion GP, Schmidt EW, Haygood MG. Proc Natl Acad Sci US A. 2017 May;114(18):E3652.

Mindapyrroles A-C, pyoluteorin analogues from a shipworm-associated bacterium. Lacerna NM 2nd, Miller BW, Lim AL, Tun JO, Robes JMD, Cleofas MJB, Lin Z, Salvador-Reyes LA, Haygood MG, Schmidt EW, Concepcion GP. J Nat Prod. 2019 Apr;82(4):1024.

Press Releases and Media:

University of Utah Health: “Science Fiction Horror Wriggles into Reality with Discovery of Giant Sulfur-Powered Shipworm”

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F o x 13

Drug Discovery in Exotic Marine Symbionts | PI: Margo Haygood, PhD

April 5, 2019April 12, 2023

A New Strategy for Treating Autoimmune Disease While Maintaining Immune Function

Although scientists have made considerable progress in treating autoimmune diseases such as type 1 diabetes and multiple sclerosis, few available treatments can stop or reverse disease progression. In addition, existing therapies cause chronic immune deficiency, limiting their usefulness. University of Utah Health investigator Mingnan Chen, PhD, and colleagues in the Department of Molecular Pharmaceutics have discovered a new therapeutic strategy that avoids immune deficiency while treating autoimmune disease. Specifically, they identified immune cells that express a key immune checkpoint receptor that drives type 1 diabetes and multiple sclerosis. The Chen lab then created an immunotoxin that selectively depletes these cells.

Treatment with the immunotoxin reverses the progression of a mouse version of multiple sclerosis and delays the onset of type 1 diabetes in mice. This treatment has two distinct advantages: it targets multiple types of autoimmune disease–causing cells, but also leaves the majority of immune cells intact after the targeted depletion. Thus, it does not cause broad immune deficiency. The treatment opens new horizons in treating autoimmune diseases.

References:

Depletion of PD-1-positive cells ameliorates autoimmune disease. Zhao P, Wang P, Dong S, Zhou Z, Cao Y, Yagita H, He X, Zheng SG, Fisher SJ, Fujinami RS, Chen M. Nature Biomedical Engineering. 2019 Apr;3(4):292-305.

Press Releases and Media:

University of Utah Health: “Novel Treatments Offer New Hope for Patients with Autoimmune Disease”

IFL Science
Business Standard

U of U Health Key Faculty Collaborators

Robert Fujinami, PhD

A New Strategy for Treating Autoimmune Disease While Maintaining Immune Function | PI: Mingnan Chen, PhD

March 21, 2019May 26, 2021

MicroRNA Regulation of Inflammation and Immunity

Role of microRNAs in cancer and disease.

MicroRNAs provide a crucial level of control for cell development and function through their post-transcriptional regulation of gene expression. Their importance is highlighted by their diverse functions in a range of cell types, including immune cells.

Pioneering studies from O’Connell and colleagues have identified two key microRNAs, termed miR-155 and miR-146a, that regulate the immune system, and therefore contribute to inflammatory disease conditions in mammals. The microRNAs lead to inflammation by acting in cells that express them and through secretion of extracellular vesicles that facilitate microRNAs delivery to distal target cells. Specifically, O’Connell and colleagues’ work has defined a link between these immunoregulatory microRNAs and diseases that include cancer, autoimmunity, and metabolic disorders.

References:

miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response. Wallace JA, Kagele DA, Eiring AM, Kim CN, Hu R, Runtsch MC, Alexander M, Huffaker TB, Lee SH, Patel AB, Mosbruger TL, Voth WP, Rao DS, Miles RR, Round JL, Deininger MW, O’Connell RM. Blood. 2017 Jun;129(23):3074.

Anti-inflammatory microRNA-146a protects mice from diet-induced metabolic disease. Runtsch MC, Nelson MC, Lee SH, Voth W, Alexander M, Hu R, Wallace J, Petersen C, Panic V, Villanueva CJ, Evason KJ, Bauer KM, Mosbruger T, Boudina S, Bronner M, Round JL, Drummond MJ, O’Connell RM. PLoS Genet. 2019 Feb;15(2):e1007970.

MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancers. Ekiz HA, Huffaker TB, Grossmann AH, Stephens WZ, Williams MA, Round JL, O’Connell RM. JCI Insight. 2019 Mar;4(6). pii: 126543.

MicroRNA Regulation of Inflammation and Immunity | PI: Ryan O'Connell, PhD

February 12, 2019May 26, 2021

Fast-acting Insulins from Cone Snails

Model showing how mini-insulin (mini-Ins, gold and green) binds human insulin receptor (hIR, powder blue, magenta and tan) and replaces key interactions made by the terminal segment of human insulin (h-Ins, black).

Faster acting human insulins are needed to improve the efficacy of diabetic insulin pumps. Over the past few years, collaborating teams led by Olivera, Safavi-Hemami, Schlegel, Yandell, and Chou have made the remarkable discovery that fish-hunting cone snails use fast-acting insulins to inactivate their prey by inducing hypoglycemia. The team characterized these toxins and used the information gained to design a new fast-acting, stable human mini-insulin analog that has more rapid onset than current competitors in porcine diabetes models.

References:

Specialized insulin is used for chemical warfare by fish-hunting cone snails. Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, Schlegel A, Imperial JS, Watkins M, Bandyopadhyay PK, Yandell M, Li Q, Purcell AW, Norton RS, Ellgaard L, Olivera BM. Proceedings of the National Academy of Sciences USA. 2015 Feb;112(6):1743.

Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor. Ahorukomeye P, Disotuar MM, Gajewiak J, Karanth S, Watkins M, Robinson SD, Flórez Salcedo P, Smith NA, Smith BJ, Schlegel A, Forbes BE, Olivera B, Hung-Chieh Chou D, Safavi-Hemami H. Elife. 2019 Feb;8. pii:e41574.

Press Releases and Media:

University of Utah Health: “Gory, Freaky, Cool: Marina Snail Venom Could Improve Insulin for Diabetic Patients”

Elife Article Highlight
Elife Podcast Highlight
ABC4
Science Daily
Popular Science
New Atlas
International Business Times

Fast-acting Insulins from Cone Snails | PI: Helena Safavi-Hemami, PhD & Danny Hung-Chieh Chou, PhD

January 17, 2019May 26, 2021

Improving Tobacco Cessation Program Utilization

Ask-Advise-Connect (AAC) increases tobacco cessation treatment enrollment 29-fold compared to a control Ask-Advise-Refer (AAR) protocol.

Tobacco cessation substantially reduces the risk of cancer and other diseases, but evidence-based tobacco cessation treatments are currently underutilized. To address this problem, Wetter and colleagues developed and tested a proactive strategy called Ask-Advise-Connect, in which the electronic health record includes supports to assess the tobacco use status of every patient at every visit, provide advice to quit, and directly and electronically link interested tobacco users with the Quitline, which then proactively calls them within 48 hours. This system yielded markedly higher rates of treatment enrollment than other approaches and is now a CDC recommended “best practice.”

References:

Ask-Advise-Connect: a new approach to smoking treatment delivery in health care settings. Vidrine JI, Shete S, Cao Y, Greisinger A, Harmonson P, Sharp B, Miles L, Zbikowski SM, Wetter DW. JAMA Intern Med. 2013 Mar;173(6):458.

The Ask-Advise-Connect approach for smokers in a safety net healthcare system: A group-randomized trial. Vidrine JI, Shete S, Li Y, Cao Y, Alford MH, Galindo-Talton M, Rabius V, Sharp B, Harmonson P, Zbikowski SM, Miles L, Wetter DW. Am J Prev Med. 2013 Dec;45(6):737.

Quitline treatment dose predicts cessation outcomes among safety net patients linked with treatment via Ask-Advise-Connect. Piñeiro B, Wetter DW, Vidrine DJ, Hoover DS, Frank-Pearce SG, Nguyen N, Zbikowski SM, Williams MB, Vidrine JI. Prev Med Rep. 2019 Jan;13:262.

Improving Tobacco Cessation Program Utilization | PI: David W. Wetter, PhD

January 2, 2019June 28, 2021

Assessing and Enhancing Blood Pressure Control Protocols

Generalizability of results from the Systolic Blood Pressure Intervention Trial (SPRINT) to the US adult population.

Adults at high risk for cardiovascular disease who receive intensive systolic blood pressure control have significantly lower rates of death and cardiovascular disease events than those who receive standard control. However, the lifetime health benefits and health care costs associated with intensive control are not known.

University of Utah Health investigators Adam Bress, PharmD, with Alfred Cheung, MD, Mark Supiano, MD, and colleagues, enhanced population health by defining what the Systolic Blood Pressure Intervention Trial (SPRINT) and the 2017 ACC/AHA blood pressure guidelines mean for clinical practice and public health. The researchers found that 1) intensive blood pressure control is cost-effective, regardless of whether the benefits were reduced after five years or persisted for the patient’s remaining lifetime, and 2) if fully implemented in eligible U.S. adults, intensive blood pressure treatment could prevent >100,000 deaths per year.

References:

Generalizability of SPRINT results to the U.S. adult population. Bress AP, Tanner RM, Hess R, Colantonio LD, Shimbo D, Muntner P. J Am Coll Cardiol. 2016 Feb 9;67(5):463.

Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (systolic blood pressure intervention trial) intensive blood pressure regimen in the United States: projections from NHANES (national health and nutrition examination survey). Bress AP, Kramer H, Khatib R, Beddhu S, Cheung AK, Hess R, Bansal VK, Cao G, Yee J, Moran AE, Durazo-Arvizu R, Muntner P, Cooper RS. Circulation. 2017 Apr; ;135 (17):1617.

Cost-effectiveness of intensive versus standard blood-pressure control. Bress AP, Bellows BK, King JB, Hess R, Beddhu S, Zhang Z, Berlowitz DR, Conroy MB, Fine L, Oparil S, Morisky DE, Kazis LE, Ruiz-Negrón N, Powell J, Tamariz L, Whittle J, Wright JT Jr, Supiano MA, Cheung AK, Weintraub WS, Moran AE; SPRINT Research Group. N Engl J Med. 2017 Aug;377(8):745.

Potential cardiovascular disease events prevented with adoption of the 2017 American College of Cardiology/American Heart Association blood pressure guideline. Bress AP, Colantonio LD, Cooper RS, Kramer H, Booth JN 3rd, Odden MC, Bibbins-Domingo K, Shimbo D, Whelton PK, Levitan EB, Howard G, Bellows BK, Kleindorfer D, Safford MM, Muntner P, Moran AE. Circulation. 2019 Jan;139(1):24.

Press Releases and Media:

University of Utah Health: “How Low to Go For Blood Pressure? Lower Target Could Affect Millions of Americans”; “Intensive Blood Pressure Control Could Prevent 100,000 Deaths Each Year”; “Two Studies Support Intensive Blood Pressure Control for Long-Term Health, Quality of Life”

TIME Magazine
The New York Times
MedPage Today
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Medscape

U of U Health Key Faculty Collaborators

Rachel Hess, MD
Alfred Cheung, MD
Srinivasan Beddhu, MD
Mark Supiano, MD
Molly Conroy, MD

Assessing and Enhancing Blood Pressure Control Protocols | PI: Adam Bress, PharmD

January 1, 2019May 26, 2021

Ovarian Cancer Subtyping to Understand Risk, Treatment, Survival, and Racial/Ethnic Disparities

Kaplan-Meir survival curves for overall survival by molecular subtype in ~3200 high grade serous ovarian cancer cases.

Ovarian cancer is the deadliest gynecologic cancer, with a five-year survival of only 47%. Treatment has remained consistent over the last several decades, using a “one size fits all” approach for the various histotypes, with minimal improvement in outcomes. Doherty and colleagues have focused on deciphering heterogeneity in ovarian cancer tumors, as a guide to the understanding of risk, treatment, survival, and racial/ethnic disparities. In a definitive paper on this topic, they used data from >28,000 cases in the Surveillance, Epidemiology, and End Results (SEER) program. The group found that histotypes, as defined by the new WHO guidelines, are associated with apparent differences in survival in the U.S. population. The most common and lethal histotype, high grade serous ovarian cancer (HGSC), is also highly variable.

As part of an international team of investigators, Doherty and colleagues have also developed a new clinical test, PrOTYPE (Predictor of high-grade serous Ovarian carcinoma molecular subTYPE), to classify HGSC into one of four known molecular subtypes associated with differential survival, and distinct biological features believed to respond differently to treatment options. PrOTYPE allows the classification of an individual patient’s tumor in real-time and has applications for research studies and clinical trials. They are also examining epidemiologic features associated with each histotype and HGSC subtype, and whether the prevalence and features of the subtypes are linked to racial/ethnic disparities in ovarian cancer outcomes.

References:

Challenges and opportunities in studying the epidemiology of ovarian cancer subtypes. Doherty JA, Peres LC, Wang C, Way GP, Green CS, Schildkraut JM. Curr Epidemiol Rep. 2017 Sep;4(3):211.

Invasive epithelial ovarian cancer survival by histotype and disease stage. Peres LC, Cushing-Haugen KL, Köbel M, Harris HR, Berchuck A, Rossing MA, Schildkraut JM, Doherty JA. J Natl Cancer Inst. 2019 Jan;111(1):60.

Ovarian Cancer Subtyping to Understand Risk, Treatment, Survival, and Racial/Ethnic Disparities | PI: Jennifer A. Doherty, PhD

January 1, 2019May 26, 2021

Defining Essential Regions of the Human Genome

Patterns of genetic variation (depicted as colored dots) from >120,000 humans revealed constrained coding regions within genes where variation does not occur in healthy individuals.

There is a longstanding interest in identifying the subset of our genome that is the most essential to life and normal development. Such regions should be under the highest purifying selection, and therefore, exhibit lower nucleotide diversity. In the case of protein-coding genes, especially strong “constraint” should be observed against protein-altering (i.e., missense, stop-gain, frameshift, etc.) variants. Prior studies have attempted to identify constrained genes, but have been unable to identify focal regions of constraint within each gene: in other words, which specific regions of protein genes are most intolerant, and therefore most likely to cause disease when mutated?

To address this question, Quinlan and colleagues studied genetic variation detected among >120,000 human exomes to reveal focal coding regions that lack variation in healthy individuals. These “constrained coding regions” (CCRs) are inferred to be under strong purifying selection and are enriched for known pathogenic variants. Perhaps the most intriguing aspect of this map of CCRs is the fact than many of the most constrained regions lie within genes that lacked prior disease association. Thus, these regions hold the promise of new disease gene discovery in the context of developmental disorders and are used to prioritize mutations in rare human diseases.

Aaron Quinlan, Ph.D. Photo credit: Charlie Ehlert

References:

A map of constrained coding regions in the human genome. Havrilla JM, Pedersen BS, Layer RM, Quinlan AR. Nat Genet. 2019 Jan;51(1):88 (cover article).

Press Releases and Media:

University of Utah Health: “Big Datasets Pinpoint New Regions to Explore the Genome for Disease“

GenomeWeb
MedicalXpress
Health News Digest

Defining Essential Regions of the Human Genome | PI: Aaron Quinlan, PhD

October 16, 2018May 26, 2021

Improved Genetic Models for Non-small-cell Lung Cancer

Cell fate lineage specifiers that determine lung tumor subtype (SOX2 and NKX2-1) control the tumor immune microenvironment by opposing CXCL5, a neutrophil recruitment chemokine.

The major types of non-small-cell lung cancers (squamous cell carcinoma and adenocarcinoma) have unique mutational drivers, that result in tumors with distinct immune microenvironments. Issues of high interest include identifying the transcription factors that determine the differences between squamous cell carcinoma and adenocarcinoma, and whether and how these two tumor types interact with and impact the immune system. To address this issue, Oliver and colleagues developed a genetic model of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and used the model to show how lineage-defining transcription factors such as Sox2 and NKX2-1 activate genes and pathways that determine different tumor immune microenvironments.

References:

The lineage-defining transcription factors SOX2 and NKX2-1 determine lung cancer cell fate and shape the tumor immune microenvironment. Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Arya R, Camolotto SA, Mosbruger TL, Stubben CJ, Conley CJ, Bhutkar A, Vahrenkamp JM, Berrett KC, Cessna MH, Lane TE, Witt BL, Salama ME, Gertz J, Jones KB, Snyder EL, Oliver TG. Immunity. 2018 Oct;49(4):764.

Press Releases and Media:

University of Utah Health: “Researchers Identify a Moving Target in Small Cell Lung Tumors”

Improved Genetic Models for Non-small-cell Lung Cancer | PI: Trudy G. Oliver, PhD

August 16, 2018May 26, 2021

Sensing and Regulating Cellular Energy Production

Western blot showing that yeast with impaired production of mitochondrial acetyl-CoA due to loss of the mitochondrial pyruvate carrier (mpc1) have impaired assembly of respiratory complexes.

Cells must decide when to expand mitochondrial capacity to accommodate increased energy demands. Rutter, Winge, and colleagues have shown that the ancient mitochondrial fatty acid synthesis system has a profound and unexpected regulatory role in driving mitochondrial biogenesis. The team showed that a potential cause originates from the scaffold protein, Acyl Carrier Protein 1 (ACP1), which functions in the building of fatty acids and also binds and activates a series of proteins required for mitochondrial biogenesis.

The binding of proteins related to this biogenesis requires that ACP1 is acylated. ACP1 acylation requires and is rate-limited by the cofactor acetyl-CoA, which acts as the universal fuel for respiration as well as the substrate for fatty acid synthesis. Thus, this system provides an elegant mechanism for sensing and creating an increased respiratory capacity to meet demand. Thus, eukaryotic cells adjust the level of active electron transport chain complexes to match the level of acetyl-CoA “fuel” available.

References:

The mitochondrial acyl carrier protein (ACP) coordinates mitochondrial fatty acid synthesis with iron sulfur cluster biogenesis. Van Vranken JG, Jeong MY, Wei P, Chen YC, Gygi SP, Winge DR, Rutter J. Elife. 2016 Aug;5. pii: e17828.

ACP acylation is an Acetyl-CoA-dependent modification required for electron transport chain assembly. Van Vranken JG, Nowinski SM, Clowers KJ, Jeong MY, Ouyang Y, Berg JA, Gygi JP, Gygi SP, Winge DR, Rutter J. Molecular Cell. 2018 Aug;71(4):567.

Sensing and Regulating Cellular Energy Production | PI: Jared P. Rutter, PhD

August 15, 2018May 26, 2021

Diaphragm Development and Congenital Hernias

Fluorescent microscope image of developing mouse diaphragm. Muscle in red, connective tissue and central tendon in green, nerves in blue.

The diaphragm is an essential mammalian skeletal muscle, as it is required for respiration and serves as a barrier between the thoracic and abdominal cavities. Unfortunately, it is also subject to developmental defects that lead to the common birth defect, congenital diaphragmatic hernias (CDH). CDH is common (1 in 3,000 births), and 50% of CDH babies die. Despite the diaphragm’s functional importance and the frequency and severity of CDH, the healthy development of the diaphragm, and what goes wrong during CDH has been poorly understood.

The Kardon lab used sophisticated mouse genetic studies to establish that the diaphragm arises from multiple embryonic tissues. One of these tissues, the pleuroperitoneal folds (PPFs), not only gives rise to the diaphragm’s muscle connective tissue and central tendon but also regulates the overall development of the diaphragm. Furthermore, they showed that genetic defects in the PPFs lead to CDH. Thus, these researchers showed that the PPFs are critical for normal diaphragm development and subject to genetic defects related to CDH. Their studies suggest future avenues for therapies to treat CDH.

Gabrielle Kardon, Ph.D. talking with Josh Hensley whose daughter had congenital diaphragmatic hernia (CDH).

References:

Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Merrell AJ, Ellis BJ, Fox ZD, Lawson JA, Weiss JA, Kardon G. Nat Genet. 2015 May;47(5):496.

Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle. Sefton EM, Gallardo M, Kardon G. Dev Biol. 2018

Press Releases and Media:

University of Utah Health: “New Insights into Little Known but Common Birth Defect: Congenital Diagphragmatic Hernia”

New York Times

Diaphragm Development and Congenital Hernias | PI: Gabrielle Kardon, PhD

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”

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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
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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
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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