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

February 4, 2020May 26, 2021

How Cells Choose to Create Energy

Schematic showing that low MPC expression in the intestinal epithelium predisposes for increased stemness and oncogenesis.

To supply their energy needs, cells typically choose between utilizing glucose in the cytoplasm (aerobic glycolysis and lactic acid fermentation) or “burning” pyruvate in the mitochondria (mitochondrial carbohydrate oxidation). Although this is arguably the most fundamental metabolic decision that cells make, before 2012 it was not clear how cells import pyruvate into mitochondria to fuel ATP production. That year, Rutter, Thummel, and colleagues identified the heterodimeric MPC1/MPC2 complex as the mitochondrial pyruvate carrier.

The group identified and explained the severe metabolic defects found in families with mpc1 gene mutations. Rutter and collaborators have subsequently shown that the choice of whether to import pyruvate has far-reaching medical implications because stem cells and most cancer cells are glycolytic (the “Warburg Effect”). They showed that this is often because cells down-regulate MPC expression, and MPC re-expression reverses the Warburg Effect, impedes tumor growth, and drives cell differentiation. These discoveries have revolutionized our understanding of the role of metabolic decisions in determining cell state and fate.

References:

A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter J. Science. 2012 Jul;337(6090):96.

A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, Egnatchik RA, Earl EG, DeBerardinis RJ, Rutter J. Molecular Cell. 2014 Nov;56(3):400.

A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC). Sandoval IT, Delacruz RG, Miller BN, Hill S, Olson KA, Gabriel AE, Boyd K, Satterfield C, Van Remmen H, Rutter J, Jones DA. Elife. 2017 Apr;6. pii: e22706.

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Schell JC, Wisidagama DR, Bensard C, Zhao H, Wei P, Tanner J, Flores A, Mohlman J, Sorensen LK, Earl CS, Olson KA, Miao R, Waller TC, Delker D, Kanth P, Jiang L, DeBerardinis RJ, Bronner MP, Li DY, Cox JE, Christofk HR, Lowry WE, Thummel CS, Rutter J. Nature Cell Biology. 2017 Sep;19(9):1027.

Regulation of tumor initiation by the mitochondrial pyruvate carrier. Bensard CL, Wisidigama DR, Olson KA, Berg JA, Krah NM, Schell JC, Bott AJ, Nowinski SM, Wei P, Dove KK, Tanner JM, Panic V, Fogarty SA, Cluntun A, Lettlova S, Earl CS, Namnath DF, Vázquez-Arregun K, Villanueva CJ, Tantin D, Murtaugh LC, Evason KJ, Ducker GS, Thummel CS, Rutter J. Cell Metabolism. 2019. Dec;Epublication ahead of print.

Press Releases and Media:

University of Utah Health: Rewiring Metabolism Slows Cancer Growth

Science Daily
Medical News Today
Medical Xpress

How Cells Choose to Create Energy | PI: Jared P. Rutter, PhD

January 11, 2020June 9, 2021

How Iron Deficiency Impairs Pancreatic β-Cell Function

Diabetes is characterized by high blood glucose levels caused by the inability of pancreatic β-cells to produce sufficient insulin to meet the body’s needs. Diabetes is driven by both genetic and environmental factors. Excess body iron is one known risk factor in the development of diabetes. Iron deficiency is associated with obesity, a known diabetes risk factor. Research in the lab of Elizabeth Leibold, PhD, showed that in mice with iron deficiency, proinsulin processing to mature insulin was impaired, resulting in reduced levels of circulating and glucose intolerance. Mice treated with iron restored insulin to normal levels and eliminated the glucose intolerance. Further biochemical studies showed the precise molecular mechanism by which iron deficiency impairs insulin production in β-cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that enhances our understanding of pathobiology of iron deficiency and diabetes, and may have therapeutic implications.

Reference:

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification. dos Santos MCF, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, Rathkolb B, Gailus-Durner V, Fuchs H, Wolf E, Rozman J, de Angelis MH, Cai WM, Rajan M, Hu J, Dedon PC, Leibold EA. Nat Commun. 2020 Jan;11(1):296.

How Iron Deficiency Impairs Pancreatic β-Cell Function | PI: Elizabeth Leibold, PhD

December 1, 2019June 15, 2021

Mechanisms of Circulatory Abnormalities and Fatigue in Patients with Cardiovascular Diseases

Premature fatigue, a hallmark of individuals with cardiovascular diseases such as heart failure or hypertension, substantially impairs the patients’ ability to effectively execute tasks of daily living. Although researchers long believed that patients’ abnormal circulatory response to physical activity contributed to this premature fatigue, they did not fully understand the mechanism(s)underlying the circulatory abnormalities. Markus Amann, PhD, and colleagues recently discovered that both heart failure and hypertension impair an important neurocirculatory control mechanism in humans—specifically, a reflex loop mediated by neural feedback from muscles to the central nervous system. This impairment results in excessive sympathetic nervous system activity, and largely accounts for the circulatory abnormalities observed during physical activities. In additional experiments, Amann’s group demonstrated that the mechanism underlying the impaired circulatory control also accounts for the premature fatigue and limited ability to execute tasks of daily living in patients with cardiovascular diseases.

References:

Group III/IV muscle afferents impair limb blood in patients with chronic heart failure. Amann M, Venturelli M, Ives SJ, Morgan DE, Gmelch B, Witman MA, Groot HJ, Wray WD, Stehlik J, Richardson RS. Int J Cardiol. 2015 June 15;174(2):368.

Exercise pressor reflex contributes to the cardiovascular abnormalities characterizing hypertensive humans during exercise. Sidhu SK, Weavil JC, Rossman MJ, Jessop JE, Buys MJ, Supiano MS, Richardson RS, Bledsoe AD, Amann M. Hypertension. 2019 December;74(6):1468.

Mechanisms of Circulatory Abnormalities and Fatigue in Patients with Cardiovascular Diseases | PI: Markus Amann, PhD

November 27, 2019May 26, 2021

Architecture of the Inner Ear

3D printing model for complex extracellular matrix. (A) PSA-lectin staining of the developing cochlea shows the complex matrix architecture of the tectorial membrane of the inner ear. (B) 3D printing model: printing of a new layer and simultaneous release of pre-established layer to build a multi-layered structure.

Normal hearing is dependent upon a highly specialized structure in the inner ear called the tectorial membrane. How this precisely organized extracellular matrix is assembled had been unknown. However, Park and colleagues showed the inner ear membrane anchors to the cell surface during development and grows one layer at a time. This process depends upon anchoring and then release of the GPI-anchored protein TECTA. Once a layer is formed, TECTA is released, and the next layer is ‘printed’ underneath it. The mechanism is similar to 3D printing and eventually results in a multi-layered architecture. This proposed 3D printing model provides novel insight into our understanding of the extracellular matrix morphogenesis process during development and tissue repair.

References:

The release of surface-anchored α-tectorin, an apical extracellular matrix protein, mediates tectorial membrane organization. Kim DK, Kim JA, Park J, Niazi A, Almishaal A, Park S. Sci Adv. 2019 Nov;5(11):eaay6300.

Press Releases and Media:

Nature Middle East

Architecture of the Inner Ear | PI: Sungjin Park, PhD

November 26, 2019May 26, 2021

Gene Expression and Health Risks

An analysis of accelerated evolution in species with highly distinctive traits reveals candidate functional genomic elements for shaping somatic mutation rate, cancer risk, digit development, immunity, glaucoma, pigmentation, and other clinical phenotypes.

An important area of research involves learning how gene expression influences health and disease risks. The parts of the genome that regulate gene expression are cis-regulatory elements. Gregg and colleagues took an unusual approach to discover these cis-regulatory elements by analyzing the genomes of species that evolved disease resistance “superpowers”. For example, elephants have large bodies with many cells and have evolved unique mechanisms to prevent cancer. By comparing the elephant genome to smaller, less cancer-resistant species, they uncovered putative master cis-regulatory elements in the genome that shape mammalian cancer resistance.

In a separate study, they studied hibernating mammals that have evolved unique controls over metabolism, obesity, and aging. By comparing their genomes to non-hibernating species, they found cis-regulatory elements that are putative master regulators of mammalian obesity, feeding, metabolism, and aging. In total, the Gregg lab has analyzed the genomes of over ten species with different biomedical superpowers, creating an atlas of cis-regulatory elements linked to clinically relevant phenotypes.

References:

Accelerated evolution in distinctive species reveals candidate elements for clinically relevant traits, including mutation and cancer resistance. Ferris E, Abegglen LM, Schiffman JD, Gregg C. Cell Rep. 2018 Mar;22(10):2742.

Parallel accelerated evolution in distant hibernators reveals candidate cis elements and genetic circuits regulating mammalian obesity. Ferris E, Gregg C. Cell Rep. 2019 Nov;29(9):2608.

Press Releases and Media:

University of Utah Health: Hibernating Mammals Arouse Hope for Genetic Solutions to Obesity, Metabolic Diseases; Mapping the Genome Jungle: Unique Animal Traits Could Offer Insight into Human Disease

NBC News
Newsweek
Genome Web
Daily Mail
International Business Times

Gene Expression and Health Risks | PI: Christopher T. Gregg, PhD

November 15, 2019May 26, 2021

How Microbes Make Drug-like Molecules

An anti-HIV peptide obtained by mining the animal microbiome.

Many life-saving drugs come from natural sources such as microbes. Learning how host organisms produce these drugs is an area of intense interest because scientists could exploit the pathways to produce more and better drug variants. Schmidt and colleagues have elucidated the mechanisms by which microbes produce one class of drug-like molecules, the Ribosomally-synthesized and Post-translationally modified Peptides (RiPPs). Bioactive RiPPs are produced from a precursor peptide, which is modified by enzymes.

The research group identified specific biosynthetic pathways that produce such discrete natural product compounds, which have potential as human therapeutics. These discoveries demonstrate how modern metagenomic methods can elucidate the vast repertoire of natural products that were inaccessible using traditional isolation methods. The insights now influence how other investigators in the natural products field tailor their investigations to discover novel drugs as potential lead therapeutics.

References

Metabolic model for diversity-generating biosynthesis. Tianero MD, Pierce E, Raghuraman S, Sardar D, McIntosh JA, Heemstra JR, Schonrock Z, Covington BC, Maschek JA, Cox JE, Bachmann BO, Olivera BM, Ruffner DE, Schmidt EW. Proc Natl Acad Sci USA. 2016 Feb;113(7):1772.

Accessing chemical diversity from the uncultivated symbionts of small marine animals. Smith TE, Pond CD, Pierce E, Harmer ZP, Kwan J, Zachariah MM, Harper MK, Wyche TP, Matainaho TK, Bugni TS, Barrows LR, Ireland CM, Schmidt EW. Nat Chem Biol. 2018 Feb;14(2):179.

The biosynthetic diversity of the animal world. Torres JP, Schmidt EW. J Biol Chem. 2019 Nov;294(46):17684.

How Microbes Make Drug-like Molecules | PI: Eric W. Schmidt, PhD

November 1, 2019May 26, 2021

An EHR Clinical Support App for Monitoring Bilirubin Levels

The ReImagine EHR app used to monitor bilirubin levels over time, alerting the clinical team when intervention is necessary.

Electronic health records (EHR) are a rich source of clinical and research data, but clinicians and researchers often cannot access this information efficiently. The Department of Biomedical Informatics has developed the ReImagineEHR initiative to improve the functionality of electronic health record systems. Faculty members del Fiol and Kawamoto led this effort by developing and implementing the infobutton international standard for clinical decision support and develop platforms that enable clinicians to obtain more information from electronic medical records with less effort. A prime example of the innovation from this group is the Neonatal Bilirubin Management Tool, which decreases physician EHR usage time and guides the prescription of phototherapy as needed, thereby improving physician efficiency and patient care.

References:

Association of an electronic health record add-on App for neonatal bilirubin management with physician efficiency and care quality. Kawamoto K, Kukhareva P, Shakib JH, Kramer H, Rodriguez S, Warner PB, Shields D, Weir C, Del Fiol G, Taft T, Stipelman CH. JAMA Netw Open. 2019 Nov;2(11):e1915343.

An EHR Clinical Support App for Monitoring Bilirubin Levels | PI: Kensaku Kawamoto, MD, PhD & Carole H. Stipelman, MD

October 22, 2019May 26, 2021

Drug-Free Macromolecular Therapeutics

DFMT exploits the selective Watson-Crick base-pairing properties of oligonucleotides to tether receptor-prebound antibodies to receptors at the cell surface.

Monoclonal antibody therapy has numerous benefits but can lack efficacy, often because monovalent binding of antibodies to specific receptors fails to translate into an active response. The Kopeček laboratory has built on their track record in polymeric drug delivery to develop a novel approach to therapeutic design, termed “Drug-Free Macromolecular Therapeutics (DFMT)”. DFMT exploits the selective Watson-Crick base-pairing properties of oligonucleotides to tether receptor-prebound antibodies to receptors at the cell surface.

This two-step self-assembly strategy uses both sequential receptor binding and clustering to broaden and strengthen antibody functions, including the anti-CD20 antibody obinutuzumab, which increases apoptotic cell death in cancer cells both in vitro and in vivo. Their second-generation DFMT combines the activation pathways of Type I and Type II antibodies into one system and will be developed into a new class of drug-free macromolecular therapeutics suitable for a broad spectrum of B-cell malignancies, including treatment-resistant tumors.

References:

Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Zhang R, Yang J, Sima M, Zhou Y, Kopeček J. Proc Natl Acad Sci USA. 2014 Aug;111(33):12181.

Backbone degradable N-(2-Hydroxypropyl)methacrylamide copolymer conjugates with gemcitabine and paclitaxel: impact of molecular weight on activity toward human ovarian carcinoma xenografts. Yang J, Zhang R, Pan H, Li Y, Fang Y, Zhang L, Kopeček J. Mol Pharm. 2017 May;14(5):1384.

Broadening and enhancing functions of antibodies by self-assembling multimerization at cell surface. Li L, Wang J, Li Y, Radford DC, Yang J, Kopeček J ACS Nano. 2019 Oct;13(10):11422.

Drug-Free Macromolecular Therapeutics | PI: Jindrich Henry Kopecek, MD

October 8, 2019May 26, 2021

Determinants of Fat Tissue Expansion

Unanticipated heterogeneity in the cell populations that comprise adipose depots.

Adipose tissue (fat) is a complicated organ that can undergo massive expansion in response to nutritional overload. The Boudina lab discovered adipose progenitors with potent anti-adipogenic potential. These cells, which are unique to visceral fat and found in both humans and mice, could explain the propensity of visceral fat to grow by hypertrophy in response to caloric excess. They also identified a set of regulatory events that control healthy adipose expansion. This finding of heterogeneity in the adipose tissue reveals potential opportunities for therapeutic intervention to enable healthy adipose expansion and combat cardiometabolic disease.

References:

Identification of a paracrine signaling mechanism linking CD34^High progenitors to the regulation of visceral fat expansion and remodeling. Buffolo M, Pires KM, Ferhat M, Ilkun O, Makaju A, Achenbach A, Bowman F, Atkinson DL, Holland WL, Amri EZ, Chaurasia B, Franklin S, Boudina S. Cell Rep. 2019 Oct;29(2):270.

Determinants of Fat Tissue Expansion | PI: Sihem Boudina, PhD

October 5, 2019June 28, 2021

Bone-Anchored Devices that Permanently Pass Through the Skin to Maximize Amputee Function

A common orthopedic approach to recreating damaged joints is to securely attach a metal implant to the patient’s own bone, a process known as osseointegration. Our research explores a new approach by engineering percutaneous osseointegration devices, in which the metal implant that pass permanently through the skin and permit connection to an external prosthetic limb when desired. The connection can not only be accomplished easily as needed; it also improves the function of the prosthesis. A team of researchers at the University of Utah has conducted a variety of engineering and animal studies of this innovative device, which culminated in the approval and successful completion of an FDA feasibility study in a population of 10 veterans with transfemoral amputations. The team is now conducting a larger multicenter trial in that population and is initiating a second feasibility study on patients with transhumeral amputation. The long-term goal of this research is to help maximize both functional recovery and quality of life among amputees.

References:

Percutaneous implants with porous titanium dermal barriers: an in vivo evaluation of infection risk. Isackson D, McGill LD, Bachus KN. Med Eng Phys. 2011 May;33(4):418. doi:10.1016/j.medengphy. 2010.11.007. Epub 2010 Dec 10. PMID: 21145778; PMCID: PMC3071885

Cortical bone response to the presence of load-bearing percutaneous osseointegrated prostheses. Jeyapalina S, Beck JP, Bachus KN, Bloebaum RD. Anat Rec (Hoboken). 2012 Sep;295(9):1437. doi: 10.1002/ar.22533. Epub 2012 Jul 16. PMID: 22807281.

Radiographic evaluation of bone adaptation adjacent to percutaneous osseointegrated prostheses in a sheep model. Jeyapalina S, Beck JP, Bachus KN, Chalayon O, Bloebaum RD. Clin Orthop Relat Res. 2014 Oct;472(10):2966. doi: 10.1007/s11999-014-3523-z. PMID: 24557934; PMCID: PMC4160482.

Progression of bone ingrowth and attachment strength for stability of percutaneous osseointegrated prostheses. Jeyapalina S, Beck JP, Bloebaum RD, Bachus KN. Clin Orthop Relat Res. 2014 Oct;472(10):2957. doi: 10.1007/s11999-013-3381-0. PMID: 24258685; PMCID: PMC4160472.

Transhumeral loading during advanced upper extremity activities of daily living. Drew AJ, Izykowski MT, Bachus KN, Henninger HB, Foreman KB. PLoS ONE. 2017 December 19;12(12): e0189418. https://doi.org/10.1371/journal.pone.0189418

Characterization and evaluation of fluoridated apatites for the development of infection-free percutaneous devices. Bennett BT, Beck JP, Papangkorn K, Colombo JS, Bachus KN, Agarwal J, Shieh JF, Jeyapalina S. Mater Sci Eng C Mater Biol Appl. 2019 Jul;100:665. doi: 10.1016/j.msec.2019.03.025. Epub 2019 Mar 12. PMID: 30948103.

Sex and laterality differences in medullary humerus morphology. Drew AJ, Tashjian RZ, Henninger HB, Bachus KN. Anat Rec (Hoboken). 2019 Oct;302(10):1709. doi: 10.1002/ar.24138. Epub 2019 May 1. PMID: 30989818; PMCID: PMC6767548.

Variation in bone response to the placement of percutaneous osseointegrated endoprostheses: A 24-month follow-up in sheep. Jeyapalina S, Beck JP, Drew A, Bloebaum RD, Bachus KN. PLoS One. 2019 Oct 25;14(10):e0221850. doi: 10.1371/journal.pone.0221850. PMID: 31652276; PMCID: PMC6814231.

Initial stability of a percutaneous osseointegrated endoprosthesis with proximal interlocking screws for transhumeral amputees. Drew AJ, Taylor CE, Tashjian RZ, Chalmers PN, Henninger HB, Bachus KN. Clin Biomech (Bristol, Avon). 2020 Feb;72:108. doi: 10.1016/j.clinbiomech.2019.12.005. Epub 2019 Dec 6. PMID: 31862604; PMCID: PMC7414792.

Estimated forces and moments experienced by osseointegrated endoprostheses for lower extremity amputees. Taylor CE, Zhang Y, Qiu Y, Henninger HB, Foreman KB, Bachus KN. Gait Posture. 2020 Jul;80:49. doi: 10.1016/j.gaitpost.2020.05.018. Epub 2020 May 20. PMID: 32485424; PMCID: PMC7417188.

Upper extremity prosthetic selection influences loading of transhumeral osseointegrated systems. Taylor CE, Drew AJ, Zhang Y, Qiu Y, Bachus KN, Foreman KB, Henninger HB. PLoS One. 2020 Aug 6;15(8):e0237179. doi: 10.1371/journal.pone.0237179. PMID: 32760149; PMCID: PMC7410272.

Replicating dynamic humerus motion using an industrial robot. Aliaj, K, Feeney GM, Sundaralingam B, Hermans T, Foreman KB, Bachus KN, Henninger HB. PLoS One. 2020 Nov 9;15(11):e0242005.

Cortical and medullary morphology of the tibia. Taylor, CE, Henninger, HB, Bachus, KN. Anat Rec. 2021 March;304(3):507. https://doi.org/10.1002/ar.24479

Press Releases and Media

University of Utah Health: “U Researchers Developing Prosthetic Implant”

DAV: “Clinical Trial Aims to Change the Lives of Amputees”; “Groundbreaking Clinical Trial Prepares for Next Phase”

U of U Health Key Faculty Collaborators:

Sarina K. Sinclair, PhD
Heath B. Henninger, PhD
Roy D. Bloebaum, PhD

Bone-Anchored Devices that Permanently Pass Through the Skin to Maximize Amputee Function | PI: Kent N. Bachus, PhD

October 1, 2019May 26, 2021

Analyzing Human Pedigrees to Advance Genetics and Health

Journal cover highlighting the first direct estimate of retrotransposition rates in whole-genome sequenced data from three-generation CEPH pedigrees.

Well curated human pedigrees like the iconic pedigrees maintained by the Centre d’Etude du Polymorphism Humain (CEPH) provide an invaluable resource for fundamental discoveries in human genetics and health. The CEPH collection includes families collected by R. White (Utah), J. Dausset (French), J. Gusella (Venezuelan), and J. Egeland (Amish). A significant and unique contribution from the University of Utah has been whole genome sequencing of the CEPH pedigrees, which has already produced two studies describing fundamental aspects of human genetics.

Quinlan, Jorde, and colleagues used these data to demonstrate that 10% of de novo human mutations are post-zygotic early embryonic events rather than inherited germline mutations, which has important implications for estimating disease risks in families. They also demonstrated that germline mutation rates vary substantially among families and that fathers contribute approximately ¾ of new single-gene mutations. The whole-genome pedigree data provided the first direct estimate of the rate at which mobile elements (“jumping genes”) insert into new locations in human genomes. These mobile elements constitute about half of the human genome and have significant effects on genetic variation and disease.

References:

Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation. Sasani TA, Pedersen BS, Gao Z, Baird L, Przeworski M, Jorde LB, Quinlan AR. Elife. 2019;8. pii: e46922.

Pedigree-based estimation of human mobile element retrotransposition rates. Feusier J, Watkins WS, Thomas J, Farrell A, Witherspoon DJ, Baird L, Ha H, Xing J, Jorde LB. Genome Res. 2019 Oct;29(10):1567 (cover article).

Press Releases and Media:

University of Utah Health: Genes Hop, Skip, and Jump to Alter the Human Genetic Code in About One In 20 Births.

Analyzing Human Pedigrees to Advance Genetics and Health | PI: Lynn B. Jorde, PhD

September 23, 2019May 26, 2021

Cellular Origins of Pancreatic Cancer

Histological sections of mouse pancreas, stained for the acinar marker Cpa1 (blue) and the tumor marker Claudin18 (brown). Re-expressing Ptf1a in tumor cells causes them to revert back into normal acinar cells.

Our pancreas has two main functions, endocrine control of blood sugar and exocrine production of the enzymes that digest our food. These enzymes are synthesized by pancreatic acinar cells and transported to the intestine through a network of pancreatic duct cells. Pancreatic cancer, the third deadliest cancer in the U.S., was previously assumed, based on histology and gene expression, to arise from duct cells.

However, research in the Murtaugh lab demonstrated that this cancer instead arises from fully differentiated acinar cells. This process requires a dramatic reprogramming of cellular function, resulting from the downregulation of the transcription factor Ptf1a, which is a rate-limiting step in pancreatic cancer development. The Murtaugh lab has found that reactivating Ptf1a in mouse and human pancreatic cancer induces re-differentiation and inhibits growth, and is pursuing this as a novel therapeutic approach.

References:

The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Krah NM, De La O JP, Swift GH, Hoang CQ, Willet SG, Chen Pan F, Cash GM, Bronner MP, Wright CV, MacDonald RJ, Murtaugh LC. Elife. 2015 Jul;4. pii 07125.

Prevention and reversion of pancreatic tumorigenesis through a differentiation-based mechanism. Krah NM, Narayanan SM, Yugawa DE, Straley JA, Wright CVE, MacDonald RJ, Murtaugh LC. Dev Cell. 2019 Sep;50(6):744.

Press Releases and Media:

University of Utah Health: “Discovery of How Cells Override Genetic Changes Could Lead to New Approaches in Pancreatic Cancer Treatment”

Cellular Origins of Pancreatic Cancer | PI: Charles Murtaugh, PhD

September 11, 2019May 26, 2021

Biological Consequences of Reduced Energy Flux and Inefficient Energy Generation

Alterations in the mitochondrial phospholipid underlie changes in mitochondrial efficiency that precede diabetes and liver and heart disease.

Energy transfer processes are never perfectly efficient. Funai and colleagues have discovered that the degree of inefficiency in cellular energy exchange, particularly during oxidative phosphorylation, has important biological implications. They found that decreased mitochondrial energy flux, such as that occurring with obesity or sedentary behavior, remodels the lipid composition of the mitochondrial inner membrane. Such aberrant changes are sufficient to decrease the efficiency of oxidative phosphorylation and promote respiratory failure in diaphragm muscle, fibrosis in the liver, hypertrophic cardiomyopathy in the heart, and defective thermogenesis in the adipose tissues. These studies suggest potential therapies for improving tissue energetics to treat diabetes and heart disease.

References:

Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission. Park H, He A, Tan M, Johnson JM, Dean JM, Pietka TA, Chen Y, Zhang X, Hsu FF, Razani B, Funai K, Lodhi IJ. J Clin Invest. 2019 Feb 1;129(2):694.

Phospholipid methylation regulates muscle metabolic rate through Ca²⁺ transport efficiency. Verkerke ARP, Ferrara PJ, Lin C, Johnson JM, Ryan TE, Maschek JA, Eshima H, Paran CW, Laing BT, Siripoksup P, Tippetts TS, Wentzler EJ, Huang H, Spangenburg EE, Brault JJ, Villanueva CJ, Summers SA, Holland WL, Cox JE, Vance DE, Neufer PD, Funai K. Nature Metabolism. 2019 Sept; 1:876.

Mitochondrial PE potentiates respiratory enzymes to amplify skeletal muscle aerobic capacity. Heden TD, Johnson JM, Ferrara PJ, Eshima H, Verkerke ARP, Wentzler EJ, Siripoksup P, Narowski TM, Coleman CB, Lin CT, Ryan TE, Reidy PT, de Castro Brás LE, Karner CM, Burant CF, Maschek JA, Cox JE, Mashek DG, Kardon G, Boudina S, Zeczycki TN, Rutter J, Shaikh SR, Vance JE, Drummond MJ, Neufer PD, Funai K. Sci Adv. 2019 Sep;5(9):eaax8352.

Press Releases and Media:

University of Utah Health: “Why Exercise? Study Points to Unappreciated Role for Lipids in Muscle Function”

Biological Consequences of Reduced Energy Flux and Inefficient Energy Generation | PI: Katsu Funai, PhD

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