Discoveries – Page 3 – Discovery and Innovation at University of Utah Health

September 3, 2019May 26, 2021

Signaling Pathways That Underlie Heart Disease

Notch signaling underlies the cardiovascular defects in the zebrafish model for Kabuki Syndrome.

Diseases affecting heart function exact an enormous toll on human health, but many of the genetic and molecular mechanisms underlying heart disease remain unknown. Yost and colleagues discovered novel roles for the same developmental signaling pathway in two seemingly unrelated sources of cardiac dysfunction: adult heart failure and embryonic heart malformation. In their first study, the team found that a unique population of heart muscle cells derived from the embryonic neural crest is necessary for healthy heart function. These cells produce a ligand for the Notch signaling receptor, Jag2b, and the absence of the cell population or the jag2b gene during development results in heart failure in adult fish.

In a second study, they found that in a zebrafish model for Kabuki Syndrome, a congenital heart developmental disorder, Notch signaling is overactive. In a result with exciting implications for human patients, they showed that pharmacological inhibition of Notch signaling could restore normal heart development. Together, these two studies have identified a common mechanism that links diverse forms of heart disease.

References:

Loss of embryonic neural crest derived cardiomyocytes causes adult onset hypertrophic cardiomyopathy in zebrafish. Abdul-Wajid S, Demarest BL, Yost HJ. Nat Commun. 2018 Nov;9(1):4603.

Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome. Serrano MLA, Demarest BL, Tone-Pah-Hote T, Tristani-Firouzi M, Yost HJ. PLoS Biol. 2019 Sep;17(9):e3000087.

Press Releases and Media:

Semantic Scholar

Signaling Pathways That Underlie Heart Disease | PI: H. Joseph Yost, PhD

September 1, 2019May 26, 2021

HIV Drug Development

Structure showing different elements of a D-peptide inhibitor (PIE12, yellow) binding to its HIV target.

Our NIH P50 CHEETAH Center supports basic research in HIV structural biology and molecular virology, with the long-term goal of identifying effective new strategies for therapies, vaccines, and cures. Fundamental studies of HIV capsid structure and function performed by Sundquist, Hill, and colleagues formed the basis for Gilead’s development of highly potent, and remarkably long-lasting HIV capsid inhibitors that support quarterly dosing. These inhibitors have now entered Phase II clinical trials. Similarly, pioneering studies of D-peptide inhibitors by Kay and colleagues produced a highly potent inhibitor of HIV entry that will enter Phase I trials in 2020.

References:

Pharmacokinetic and chemical synthesis optimization of a potent D-peptide HIV entry inhibitor suitable for extended-release delivery. Redman JS, Francis JN, Marquardt R, Papac D, Mueller AL, Eckert DM, Welch BD, Kay MS. Molecular Pharmacology. 2018 Mar;15(3):1169.

A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. Yant SR, Mulato A, Hansen D, Tse WC, Niedziela-Majka A, Zhang JR, Stepan GJ, Jin D, Wong MH, Perreira JM, Singer E, Papalia GA, Hu EY, Zheng J, Lu B, Schroeder SD, Chou K, Ahmadyar S, Liclican A, Yu H, Novikov N, Paoli E, Gonik D, Ram RR, Hung M, McDougall WM, Brass AL, Sundquist WI, Cihlar T, Link JO. Nature Medicine. 2019 Sep;25(9):1377.

Press Releases and Media:

POZ Newsletter
Fierce Biotech
Bloomberg Business

HIV Drug Development | PI: Wesley I. Sundquist, PhD, Michael S. Kay, MD, PhD & Christopher P. Hill, DPhil

September 1, 2019May 26, 2021

Neuronal Circuits that Modulate Pain and Defensive Responses

The axons of oxytocin-producing neurons (cyan) interact with brainstem pre-motor neurons (magenta) that drive escape responses.

Understanding pain-processing mechanisms and the neural circuits involved is central to developing new therapeutic strategies for the treatment of pain. The Douglass lab investigated brain regions that modulate behavioral responses to noxious stimuli in zebrafish. They showed that oxytocin-producing neurons in the hypothalamus are central mediators of the behavioral response to pain, recruit targets in the brainstem that drive escape responses, and function as neuromodulators. This specialized sensorimotor circuit is essential for mediating defensive responses to pain- and injury-causing stimuli.

Adam Douglass, Ph.D. Photo credit: Charlie Ehlert

References:

Zebrafish oxytocin neurons drive nocifensive behavior via brainstem premotor targets. Wee CL, Nikitchenko M, Wang WC, Luks-Morgan SJ, Song E, Gagnon JA, Randlett O, Bianco IH, Lacoste AMB, Glushenkova E, Barrios, JP, Schier AF, Kunes S, Engert F, Douglass AD. Nat Neurosci. 2019 Sep;22(9):1477.

Press Releases and Media:

University of Utah Health: “Oxytocin: An Interplay between Pleasure and Pain”

Neuronal Circuits that Modulate Pain and Defensive Responses | PI: Adam Douglass, PhD

August 13, 2019October 13, 2021

Generation and Treatment of Antibiotic Resistance

Bacteria can transfer genes conferring antibiotic resistance among strains infecting a single patient. To combat antibiotic resistance, researchers screened for drugs that can be repurposed to amplify the activity of existing antibiotics and inhibit resistant bacteria.

Antibiotics are responsible for the most significant increase in lifespan in human history. However, microbes are becoming resistant to antibiotics at an alarming rate. For example, uncontrolled drug-resistant infections can lead to recurrent urinary tract infections, sepsis, and even death. The Mulvey lab found that microbes within a single colonized site, such as the human bladder, can pass antibiotic resistance genes back and forth, propagating resistance as the infecting microbes evolve in response to serial antibiotic treatment. To improve potential treatments, the Brown lab developed methods to rapidly identify drugs that interact with existing antibiotics to increase drug efficacy. Exploiting these potentiating interactions between existing drugs allows us to expand our drug repertoire by drug repurposing – using drugs already approved by the FDA for other indications – which bypasses expensive and time-consuming clinical trials.

References:

High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance. Wambaugh MA, Shakya VPS, Lewis AJ, Mulvey MA, Brown JCS. PLoS Biol. 2017 Jun;15(6):e2001644.

Population dynamics of an Escherichia coli ST131 lineage during recurrent urinary tract infection. Forde BM, Roberts LW, Phan MD, Peters KM, Fleming BA, Russell CW, Lenherr SM, Myers JB, Barker AP, Fisher MA, Chong TM, Yin WF, Chan KG, Schembri MA, Mulvey MA, Beatson SA. Nat Commun. 2019 Aug;10(1):3643.

Press Releases and Media:

University of Utah Health: “Finding the Perfect Match: A New Approach to Battle Drug-Resistant Bacteria”

The Atlantic
Phys.org
Science Daily
Lab Manager Magazine

Generation and Treatment of Antibiotic Resistance | PI: Matthew A. Mulvey, PhD & Jessica C. Brown, PhD

August 2, 2019May 26, 2021

Structures and Mechanisms of Protein Remodeling Machines

Cdc48 AAA ATPase unfolding a protein substrate.

When a cellular protein has done its job or lost its utility, it should be removed, recycled, or remodeled. These tasks are performed by members of the ubiquitous family of AAA ATPases (ATPases associated with diverse cellular activities) that convert the energy of ATP hydrolysis into mechanical forces that can unfold protein aggregates, degrade unwanted proteins, and remodel protein complexes. To learn how AAA ATPases unfold proteins, Hill, Shen, Sundquist, and colleagues used electron cryomicroscopy to determine structures and elucidate the common mechanisms of several different AAA ATPases in complex with their polypeptide substrates. The team found that each enzyme forms a hexameric ring shaped like a lock washer, with the substrate in the central pore.

References:

Structural basis of protein translocation by the Vps4-Vta1 AAA ATPase. Monroe N, Han H, Shen PS, Sundquist WI, Hill CP. Elife. 2017 Apr;6. pii: e24487.

The AAA ATPase Vps4 binds ESCRT-III substrates through a repeating array of dipeptide-binding pockets. Han H, Monroe N, Sundquist WI, Shen PS, Hill CP. Elife. 2017 Nov;6. pii: e31324.

Structure of Vps4 with circular peptides and implications for translocation of two polypeptide chains by AAA+ ATPases. Han H, Fulcher JM, Dandey VP, Iwasa JH, Sundquist WI, Kay MS, Shen PS, Hill CP. Elife. 2019 Jun;8. pii: e44071.

Structure of the Cdc48 segregase in the act of unfolding an authentic substrate. Cooney I, Han H, Stewart MG, Carson RH, Hansen DT, Iwasa JH, Price JC, Hill CP, Shen PS. Science. 2019 Aug;365(6452):502.

Press Releases and Media:

University of Utah Health: Researchers Solve How Cells Unfold Proteins

ALS News

Structures and Mechanisms of Protein Remodeling Machines | PI: Christopher P. Hill, DPhil & Peter Shen, PhD

August 1, 2019May 26, 2021

Pinpointing Environmental Sources of Pediatric Asthma

The Phenome; a combination of the genome and the exposome.

Identifying the sources that trigger pediatric asthma is critical for successful therapeutic interventions. The collaborative PRISMS project, led by College of Nursing Associate Professor Kathy Sward, paired Utah families with asthmatic children with faculty from the University of Utah College of Nursing, the Department of Biomedical Informatics within the School of Medicine (Facelli and Gouripeddi), The College of Engineering, and The College of Mines and Earth Sciences. The University scientists collaborated with the families to develop a biomedical informatics platform to crowdsource and link air quality data with personal health monitoring data and other data resources to pinpoint environmental causes of patient symptoms.

References:

Utah PRISMS informatics ecosystem, R. Gouripeddi, V. Tiase, S. Collingwood, J. Facelli, K. Sward, ISES 2018 Technology and Sensor Fair, The Joint Annual Meeting of the International Society of Exposure Science and the International Society for Environmental Epidemiology (ISES-ISEE 2018), Ottawa, Canada, Aug, 2018.

An architecture for metadata-driven integration of heterogeneous sensor and health data for translational exposomic research, R. Gouripeddi, L. Tran, R. Madsen, T. Gangadhar, P. Mo, N. Burnett, R. Butcher, K. Sward, J. Facelli, IEEE International Conference on Biomedical and Health Informatics (BHI’19), Chicago, IL, USA, May, 2019.

Developing a specification for representing exposure health semantics, R. Gouripeddi, R. Habre, and the PRISMS Data Modeling Working Group, The International Societies of Exposure Science (ISES) and Indoor Air Quality and Climate (ISIAQ), Kaunas, Lithuania, Aug, 2019

Press Releases and Media:

University of Utah Health: “Technology to Crowdsource Complex Triggers of Pediatric Asthma”

Knowable Magazine
Science Daily

Pinpointing Environmental Sources of Pediatric Asthma | PI: Katherine Sward, PhD, RN

July 26, 2019May 26, 2021

Commensal Microbes That Help Prevent Metabolic Disease

Our intestines are colonized by a vast consortium of bacteria, viruses, and fungi that we now know have essential influences on gut health. Gut microbes are also instrumental for promoting the development of a mature immune system, but in turn, host immunity influences the types and functions of these commensal organisms. Research in the Round lab has recently shown that intestinal antibody responses select for specific organisms within the gut that prevent metabolic disease by limiting fat absorption within the intestine. In the absence of appropriate immunity in the gut, these protective microbes are lost, and hosts develop obesity and insulin resistance. Thus, health depends on a delicate balance between our immune system and resident gut microbes.

References:

MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection.Kubinak JL, Stephens WZ, Soto R, Petersen C, Chiaro T, Gogokhia L, Bell R, Ajami NJ, Petrosino JF, Morrison L, Potts WK, Jensen PE, O’Connell RM, Round JL. Nat Commun. 2015 Oct;6:8642.

Causal effects of the microbiota on immune-mediated diseases.Round JL, Palm NW. Sci Immunol. 2018 Feb;3(20). pii: eaao1603.

Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model.Libbey JE, Sanchez JM, Doty DJ, Sim JT, Cusick MF, Cox JE, Fischer KF, Round JL, Fujinami RS. Benef Microbes. 2018 Apr;9(3):495.

T cell-mediated regulation of the microbiota protects against obesity.Petersen C, Bell R, Klag KA, Lee SH, Soto R, Ghazaryan A, Buhrke K, Ekiz HA, Ost KS, Boudina S, O’Connell RM, Cox JE, Villanueva CJ, Stephens WZ, Round JL. Science. 2019 Jul;365(6451). pii: eaat9351.

Press Releases and Media:

University of Utah Health: These Gut Bacteria Prevent Obesity in Mice. What Could That Mean for Us?

The Atlantic
Science Daily
Health Medicine Network
Medical XPress

Commensal Microbes That Help Prevent Metabolic Disease | PI: June L. Round, PhD

July 24, 2019May 30, 2025

Prosthetic Limbs with Neural Connections

For the more than two million people in the United States who have lost a limb, prostheses can restore some function, but never really replace a missing arm or leg. U scientists have been working toward better prosthetic limbs for decades, with the development of technology that connects an artificial limb directly to the user’s nervous system so they can control its movements with their thoughts. More recently, Jacob George, PhD, director of the NeuroRobotics Lab, and colleagues have engineered the system to send signals back to the brain so the arm can transmit sensations of touch.

A state-of-the-art prosthesis called the LUKE Arm is powered by this technology. The LUKE Arm integrates with the nervous system through implanted sensors that tap into existing electrical signals from nerves and muscles. Artificial intelligence translates signals from the nerves and muscles into movement and translates physical forces on the artificial hand into a sense of touch. Sensations from the device give users the feedback they need to handle delicate objects or pick things up without looking at them. Early testers reported experiencing a sense of embodiment with the new limb.

References:

Biomimetic sensory feedback through peripheral nerve stimulation improves dexterous use of a bionic hand. George JA, Kluger DT, Davis TS, Wendelken SM, Okorokova EV, He Q, Duncan CC, Hutchinson DT, Thumser ZC, Beckler DT, Marasco PD, Bensmaia SJ, Clark GA. Sci Robot. 2019 Jul 24;4(32):eaax2352. doi: 10.1126/scirobotics.aax2352.

A portable, programmable, multichannel stimulator with high compliance voltage for noninvasive neural stimulation of motor and sensory nerves in humans. Trout MA, Harrison AT, Brinton MR, George JA. Sci Rep. 2023 Mar 1;13(1):3469. doi: 10.1038/s41598-023-30545-8.

Long-term performance of Utah slanted electrode arrays and intramuscular electromyographic leads implanted chronically in human arm nerves and muscles. George JA, Page DM, Davis TS, Duncan CC, Hutchinson DT, Rieth LW, Clark GA. J Neural Eng. 2020 Oct 31;17(5):056042. doi: 10.1088/1741-2552/abc025.

Prosthetic Limbs with Neural Connections | PI: Jacob George, PhD

July 1, 2019January 31, 2022

Improved Prognostic Testing for Patients with Triple Negative Breast Cancer

Kaplan-Meier curve that stratifies patients in the training set based on the Immune Activation Score threshold that provides 95% specificity.

Approximately 40% of patients with stage I-III triple-negative breast cancer (TNBC) have recurrences after standard treatment, whereas the remaining 60% experience long-term disease-free survival. However, there are currently no clinical tests to assess the risk of recurrence in TNBC patients. To address this issue, Varley and colleagues developed a multigene MHCII Immune Activation Assay to allow clinical testing for the prognosis of recurrence of triple-negative breast cancer patients. This assay identifies TNBC patients with a low risk of recurrence whose tumors express factors like MHC II pathway components, which promote immune infiltration and responses that reduce relapse and enhance survival. This work addressed a critical need for prognostic biomarker tests that enable precision medicine for TNBC patients.

References:

Expression of the MHC class II pathway in triple-negative breast cancer tumor cells is associated with a good prognosis and infiltrating lymphocytes. Forero A, Li Y, Chen D, Grizzle WE, Updike KL, Merz ND, Downs-Kelly E, Burwell TC, Vaklavas C, Buchsbaum DJ, Myers RM, LoBuglio AF, Varley KE. Cancer Immunol Res. 2016 May;4(5):390.

A multigene assay determines risk of recurrence in patients with triple-negative breast cancer. Stewart RL, Updike KL, Factor RE, Henry NL, Boucher KM, Bernard PS, Varley KE. Cancer Res. 2019 Jul;79(13):3466.

Press Releases and Media:

Huntsman Cancer Institute: “Determining Risk of Recurrence in Triple-Negative Breast Cancer”

Improved Prognostic Testing for Patients with Triple Negative Breast Cancer | PI: Katherine E. Varley, PhD

July 1, 2019May 26, 2021

Developing New Chemical Reactions that Can Be Performed in Living Cells

Dissociative biorthogonal reactions allow for chemical control of the release of bioactive agents and reporter probes.

The development of bioorthogonal chemical reactions—chemical reactions that can be conducted in living cells—has been one of the most significant areas of advancement in chemistry in recent years. Bioorthogonal reactions that join molecules together, such as “click chemistry,” have created a revolution in biomedical research. However, there are fewer bioorthogonal reactions that can split molecules. Franzini and colleagues have developed a series of highly efficient chemical reactions, termed “dissociative bioorthogonal reactions”, that do just that. These new reactions hold promise for enabling new targeted therapies and highly-sensitive diagnostic tools.

References:

Bioorthogonal removal of 3-isocyanopropyl groups enables the controlled release of fluorophores and drugs in vivo. Tu J, Xu M, Parvez S, Peterson RT, Franzini RM. J Am Chem Soc. 2018 Jul;140(27):8410.

Stable, reactive, and orthogonal tetrazines: dispersion forces promote the cycloaddition with isonitriles. Tu J, Svatunek D, Parvez S, Liu AC, Levandowski BJ, Eckvahl HJ, Peterson RT, Houk KN, Franzini RM. Angew Chem Int Ed Engl. 2019 Jul;58(27):9043.

Developing New Chemical Reactions that Can Be Performed in Living Cells | PI: Raphael Franzini, PhD

July 1, 2019May 26, 2021

The Role of Cholesterol in Activating a Key Cellular Signaling Pathway

(A) Cholesterol (yellow) binds and activates Smoothened (green) via a tunnel to the membrane inner leaflet (outlined in red.) (B) Clinical anticancer drugs block Smoothened by clashing with and displacing the bound cholesterol, suggesting new strategies to design more effective inhibitors.

Hedgehog signaling promotes embryonic development and, when aberrant, can lead to malignancies. The seven-transmembrane transducer Smoothened (SMO) occupies a key node in this pathway and is activated by cholesterol. However, how smoothened binds cholesterol and activates SMO had not been determined. A crystal structure by Myers and colleagues has revealed how cholesterol binds and activates SMO. Remarkably, the cholesterol-binding site resides within a pocket deep inside the seven-transmembrane domain, rather than on a surface location, as proposed previously. This insight suggests new strategies for overcoming clinical resistance to SMO inhibitors.

References:

Smoothened stimulation by membrane sterols drives Hedgehog pathway activity. Deshpande I, Liang J, Hedeen D, Roberts KJ, Zhang Y, Ha B, Latorraca NR, Faust B, Dror RO, Beachy PA, Myers BR, Manglik A. Nature. 2019 Jul;571(7764):284.

Press Releases and Media:

University of Utah Health: “Possible ‘Achilles Heel’ Discovered in Developing Better Drug Treatment in Cancers with Overactive Smoothened Protein”

The Role of Cholesterol in Activating a Key Cellular Signaling Pathway | PI: Benjamin R. Myers, PhD

May 5, 2019July 6, 2021

Finding New Ways to Treat Kidney Disease

Chronic kidney disease affects millions of people in the U.S. and worldwide; however, current treatments are not highly effective. Many factors contribute to chronic kidney disease, including diabetes, hypertension, autoimmune disorders, and others. Research in the lab of University of Utah Health investigator Donald Kohan, MD, PhD, used genetically engineered mice to help identify a peptide, endothelin-1, and its receptor, ETA, as key regulators of blood pressure and kidney function in health. Kohan and his colleagues also helped determine that kidney ET-1 production is increased in many kidney diseases and, through activation of ETA receptors on most kidney cell types, leads to inflammation, scarring and decreased kidney function.

Together with national and international collaborators, they have translated these studies into clinical trials demonstrating that blocking the ETA receptor protects kidney function in individuals with type 2 diabetes mellitus. These trials with ETA receptor antagonists are now being extended into other forms of chronic kidney disease. Targeting the endothelin-1/ETA receptor system represents a promising approach to the treatment of chronic kidney disease.

References:

Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. Ahn D, Ge Y, Stricklett PK, Gill P, Taylor D, Hughes AK, Yanagisawa M, Miller L, Nelson RD, Kohan DE. J Clin Invest. 2004 Aug;114(4):504-511.

Regulation of blood pressure and salt homeostasis by endothelin. Kohan DE, Inscho E, Rossi N, Pollock DM. Physio Rev. 2011 Jan;91(1):1-77.

Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya U, Andress DL. J Am Soc Nephrol. 2011 Apr;22(4):763-772.

Atrasentan and renal events in type 2 diabetes with chronic kidney disease (SONAR): a double-blind, randomized, placebo-controlled trial. Heerspink HJ, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou F-F, Kitzman DW, Kohan DE, Makino H, McMurray J, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D. Lancet. 2019 May;393(10184):1937-1947.

Finding New Ways to Treat Kidney Disease | PI: Donald Kohan, MD, PhD

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”

Jeopardy
New York Times
Washington Post
CBS News
Smithsonian
National Geographic
Wired
Popular Science
Newsweek
BBC
The Telegraph
The Australian
KSL
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
WebMD
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