News

Janssen-Heininger, Anathy & Team's Study Demonstrates Potential Lung Fibrosis Therapy

July 11, 2018 by Jennifer Nachbur

New translational research led by UVM Professor Yvonne Janssen-Heininger, Ph.D., demonstrates a novel biological therapeutic candidate for regressing pulmonary fibrosis in a difficult-to-treat preclinical model of the disease, providing much-needed hope for the roughly 150,000 Americans suffering from this devastating condition.

Yvonne Janssen-Heininger, Ph.D., UVM Professor of Pathology & Laboratory Science. (Photo: Medical Communications)

New translational research, published in Nature Medicine, demonstrates a novel biological therapeutic candidate for regressing pulmonary fibrosis in a difficult-to-treat preclinical model of the disease, providing much-needed hope for the roughly 150,000 Americans suffering from this devastating condition.

A chronic, progressive disease marked by lung scarring that impedes breathing and the flow of oxygen to the bloodstream, idiopathic pulmonary fibrosis (IPF) results in approximately 40,000 deaths each year in the U.S. alone. Believed to be associated with aging, the disease is diagnosed annually in approximately 40,000 individuals between 40 and 70 years of age. Survival is typically only three to five years after diagnosis.

This study included an examination of IPF patient lung tissue, transgenic mouse models and direct administration of a therapy based off an enzyme called glutaredoxin-1 – or GLRX – to the airways of murine models of IPF. GLRX repairs damaged proteins and is inactivated in the lungs of IPF patients and results in poor lung function. Senior study author Yvonne Janssen-Heininger, Ph.D., and first author Vikas Anathy, Ph.D., of the University of Vermont’s Larner College of Medicine, and colleagues are inventors on a patent for GLRX, granted to the University of Vermont.

Though the exact mechanisms responsible for IPF have yet to be determined, oxidative stress is believed to play a critical role in modifying and altering the function of proteins or enzymes in various diseases, including IPF. However, the therapeutic potential for reversing the oxidative stress mediated modification of proteins was unknown. Janssen-Heininger and colleagues have discovered that GLRX is capable of reversing the oxidation of proteins, preventing the death of lung cells and ultimately, regressing pulmonary fibrosis in experimental models. The researchers believe that these positive effects raise the potential of GLRX as a therapeutic agent for IPF, which currently has limited treatment options.   

“This provides a strong rationale to develop inhaled glutaredoxin as a possible therapy for patients with lung fibrosis,” says Janssen-Heininger. She and the study authors state that further investigation will be needed to gain a deeper understanding of the activity associated with GLRX.

In addition to Janssen-Heininger and Anathy, coauthors on the study include: Karolyn Lahue; David Chapman; Shi Chia; Dylan Casey; Reem Aboushousha; Jos van der Velden; Evan Elko; Sidra Hoffman; David McMillan; Jane Jones; James Nolin; Sarah Abdalla; Robert Schneider; David Seward; Elle Roberson; Matthew Liptak; Morgan Cousins; Kelly Butnor; Douglas Taatjes; Ralph Budd; Charles Irvin; Ye-Shih Ho; Razq Hakem; Kevin Brown; Reiko Matsui; Markus Bachschmid; Jose L. Gomez; Naftali Kaminski; and Albert van der Vliet.

This therapy is being developed in collaboration with Celdara Medical, LLC, of Lebanon, N.H. and with support from the National Heart, Lung and Blood Institute of the National Institutes of Health under award numbers R44 HL129593-01 and R35HL135828.

Of note:

In a recent Nature Methods paper, Doug Taatjes, Ph.D., Director of the Microscopy Imaging Center, and the Center for Biomedical Shared Resources at the Larner College of Medicine, together with colleagues from the international consortium QUAREP-LiMi, proposed a set of standardized community-developed checklists to assist researchers, reviewers, and journal editors with the goal of increasing the clarity and reproducibility of image figures and their analyses. The hope is that many journals will adopt these guidelines as part of their “Instructions for Authors”—providing a succinct and easy to use checklist for authors when compiling images for reproduction and descriptions of image analyses performed. (11/2023) (from the LCOM Newsletter)

Agilent Lab Visit 01.25.2023 editsThe RBP group took a tour of the new Agilent Laboratory for Chemical Analysis in Discovery Hall. "This new lab is a state-of-the-art instrumentation facility available to the UVM and business communities." (2023)

Congratulations to Dr. Arti Shukla, co-author on the manuscript "Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers" published in the journal Cell. Read the paper

Please join Dr. Yvonne Janssen-Heininger in congratulating Wyatt Chia on his successful thesis defense. Congratulations, Dr. Wyatt Chia, Ph.D.!!!

Please join Dr. Vikas Anathy in congratulating Nicolas Chamberlain and Dr. Emily Nakada.

Nicolas Chamberlain a PhD student recently published a paper entitled “Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics” in the journal Redox Biology (PMID 30735910). His abstract to be presented at the American Thoracic Society (ATS) conference was chosen to receive an abstract scholarship. The scholarship includes a full in-training registration to the 2019 ATS International Conference in Dallas, Texas. 

Dr. Emily Nakada was a post-doctoral fellow in our group. Her manuscript entitled “Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers” has been recently accepted in the journal JCI Insight.

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Please join Dr. Yvonne Janssen-Heininger in congratulating Allison Manuel and Evan Elko.

Dr. Allison Manuel is a post-doctoral fellow in our group.  Her abstract to be presented at the American Thoracic Society conference was chosen to receive an Abstract Scholarship . The scholarship includes a full In-Training Registration to the 2019 ATS International Conference in Dallas, Texas.   

Evan Elko is a PhD student. He just received notice that his F31 NIH application entitled: “Role of peroxiredoxin-4 in Idiopathic Pulmonary Fibrosis”  will be funded.  

Congratulations to Evan and Allison. 

                  ______________________________

Christopher Dustin and Caspar Schiifers, students in Dr. Albert van der Vliet's lab, each won a Young Investigator Award for their presentations at the SRFBM conference in Chicago. (Nov 2018)

SRFBM conference 2018

[photo left to right: students:C. Dustin, C. Schiffers, SRFBM president F. Domann, principal investigator A. van der Vliet]


Announcements

Congratulations to Dr. Yvonne Janssen-Heininger, Ph.D., on receiving the Gender Equity Outstanding Achievement in Medicine & Science Award at the 5th Annual Celebration of Gender Equity in Medicine and Science Awards. (3/2024)

Congratulations to Dr. Brian Cunniff, Ph.D., assistant professor of pathology and laboratory medicine, the team in the Cunniff Lab, and industry partner , RS Oncology, on having their novel therapy enter Phase 2 Clinical trials. Read more here Milestone for UVM-developed cancer drug. (2/2024)

Congratulations to Brian Cunniff, Ph.D., Assistant Professor Pathology and Laboratory Medicine, on being awarded a $1.6 million R01 grant by the National Institute of General Medical Sciences to study the role of mitochondrial trafficking in regulating cell migration, a key feature of metastatic tumors. (09/2023) 

Congratulations to the following RBP members on receiving research support funds in April 2023. Recipients were: Yvonne Janssen-Heininger, Ph.D., $15,000 for a joint initiative between RBP, UVM Cancer Center, and faculty in the Department of Chemistry. Megan Tarte $745 for Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease Conference. Albert van der Vliet, Ph.D., $14,400 for Redox processes in macrophage activation in IPF. (9/2023)

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A new study Yvonne Janssen-Heininger, Ph.D., professor of pathology and laboratory medicine, and colleagues published in Nature takes a deep dive into unraveling the oxidative vulnerabilities of each of the cysteines of glutaredoxin, which is important in protection from fibrosis but gets inactivated via oxidative mechanisms. The team leveraged computational chemistry approaches and experimental validation using a new assay specifically designed for this purpose. (8/2023- Larner College of Medicine Newsletter)

RBP Retreat Meeting room (2)

RBP elevator pitch winnersWinning team-Project Proposal (2)

A very successful Inaugural Redox Biology and Pathology Retreat was held recently at the Courtyard Marriott in Burlington. The day resulted in new collaborations and connections spanning, medicine, biology, and chemistry. The images show attendees in the meeting space, our individual elevator pitch winners- Dr. Reem Aboushousha, Dr. Rob Hondal, and Maurice Newton, and our $15,000 research project design winning team.(6/2023)           

vandervliet-habibovic420x280A new study by Albert van der Vliet, Ph.D., professor of pathology and laboratory medicine, and a team of University of Vermont (UVM) researchers is honing in on why people with asthma often have worse symptoms if they are obese. This new research demonstrates that the gene DUOX1 likely contributes to the connection between obesity and asthma.  The research was published ahead of print in the American Journal of Physiology-Lung Cellular and Molecular Physiology and was highlighted as an APSselect article for March 2023. Albert van der Vliet, Ph.D., was the senior author on the paper, along with department of pathology and laboratory medicine coauthors Aida Habibovic, lab research technician;Litiele Cruz, Ph.D., visiting scholar; Vikas Anathy, Ph.D., associate professor; University Distinguished Professor Yvonne Janssen-Heininger, Ph.D.; and additional team members and authors from UVM. Read the full LCOM News story LCOM News (4/2023)

Congratulations to the following recipients that received pathology research support funding. Nathaniel Shannon in Brian Cunniff's, Ph.D., lab was awarded $1800 towards the cost of travel to the 2022 Annual Meeting of the Society for Redox Biology and Medicine (SfRBM). Litiele Cruz, Ph.D., and faculty mentor Albert van der Vliet, PhD., were awarded $2622 for her project "Characterization of Laminin Oxidative Modifications by Peroxidasin in Pulmonary Fibrosis". Nels Olson, PhD., MPH., $14,582 for the purchase of an Agilent BioTek 405 TS Touch Microplate Washer, Model 405 TSRS. Ashley Volaric M.D., Joanna Conant M.D., and David Seward, M.D, Ph.D., were awarded $13,680 for their project, "The Effect of Epstein Barr Virus Latency on Cellular DNA Methylation Profile of Diffuse Large B Cell Lymphoma". (3/2023)

Albert in JapanCongratulations to Dr. Albert van der Vliet, Ph.D., professor of pathology and laboratory medicine, for being selected as an Invited Fellow to Tohoku University in Sendai, Japan, to participate in research in the laboratory of Takaaki Akaike, M.D., Ph.D., professor of environmental medicine and molecular toxicology. The invitational fellowship relates to a Tohoku University initiative that allows Tohoku faculty members to host invited researchers to promote collaborative research in the host lab for up to three months. The objective is to promote joint publications and expand international collaborations. Dr. van der Vliet's visit coincided with a medley of scientific meetings and symposia collectively termed  Redox Week In Sendai 2022 and held October 27-November 1, 2022. The events brought together leading scientists from around the world in the specific research fields of nitric oxide biology, polysulfur biochemistry, and biology. Van der Vliet was co-organizer and speaker at one of the symposiums, and Yvonne Janssen-Heininger, Ph.D., and Brian Cunniff, Ph.D., both professors of pathology and laboratory medicine, also participated as invited speakers. Additional Japanese federal funding supports the exchange of invited researchers, graduate students, and post-doctoral scholars to collaborate on research. Read more about the redox research collaboration  between UVM and Tohoku University. (01/2023)

Publications

"P. aeruginosa tRNA-fMet halves secreted in outer membrane vesicles suppress lung inflammation in Cystic Fibrosis." Li Z, Barnaby R, Nymon AB, Roche C, Koeppen K, Ashare A, Hogan DA, Gerber SA, Taatjes DJ, Hampton TH, Stanton BA. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2024 Mar 5. doi: 10.1152/ajplung.00018.2024. Online ahead of print. PMID: 38440830

"Identification of tyrosine brominated extracellular proteins in normal and fibrotic lung tissues." Cruz LC, Habibovic A, Dempsey B, Massafera MP, Janssen-Heininger YMW, Lin MJ, Hoffman ET, Weiss DJ, Huang SK, van der Vliet A, Meotti FC. Redox Biology. 2024 Feb 23;71:103102. doi: 10.1016/j.redox.2024.103102. PMID: 38430684

"ROS production by mitochondria: function or dysfunction?" Palma FR, Gantner BN, Sakiyama MJ, Kayzuka C, Shukla S, Lacchini R, Cunniff B, Bonini MG. Oncogene. 2023 Dec 11. doi: 10.1038/s41388-023-02907-z. Epub ahead of print. PMID: 38081963

"Fingerprint of the oxido-reductase ERO1: A protein disulfide bond producer and supporter of cancer." Zito E, Guarrera L, Janssen-Heininger YMW. Biochimica et biophysica acta. Reviews on Cancer. 2023 Nov 24;1879(1):189027. doi: 10.1016/j.bbcan.2023.189027. Online ahead of print. PMID: 38007054

"Bariatric Surgery Decreases the Capacity of Plasma from Obese Asthmatic Subjects to Augment Epithelial Cell Pro-Inflammatory Cytokine Production." Pena-Garcia PE, Fastiggi VA, Mank MM, Ather JL, Garrow OJ, Anathy V, Dixon AE, Poynter ME. American Jounral of Physiology. Lung Cellular and Molecular Physiology. 2023 Nov 21. doi: 10.1152.ajplung.00205.2023. Online ahead of print. PMID: 37988602

"Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma." Maia-Silva D, Schier AC, Skopelitis D, Kechejian V, Alpsoy A, Liverpool J, Taatjes DJ, Vakoc CR. bioRxiv. 2023 Oct 27:2023.10.24.563848. doi: 10.1101/2023.10.24.563848. Preprint. PMID: 37961243

"Glutaredoxin attenuates glutathione levels via deglutathionylation of Otub 1 and subsequent destabilization of system xC." Aboushousha R, van der Velden J, Hamilton N, Peng Z, MacPherson M, Erickson C, White S, Wouters EFM, Reynaert NL, Seward DJ, Li J, Janssen-Heininger YMW. Science Advances. 2023 Sep 15;9(37):eadi5192. doi: 10.1126/sciadv.adi5192. Epub 2023 Sep 13. PMID: 37703360

"Obesity exacerbates influenza-induced respiratory disease via the arachidonic acid-p38 MAPK pathway." Chandrasekaran R, Morris CR, Butzirus IM, Mark ZF, Kumar A, Souza De Lima D, Daphtary N, Aliyeva M, Poynter ME, Anathy V, Dixon AE. Frontiers in Pharmacology. 2023 Aug 23;14:1248873. doi: 10.3389/fphar.2023.1248873. eCollection 2023. PMID: 37680710

"WR1065 conjugated to thiol-PEG polymers as novel anticancer prodrugs: broad spectrum efficacy, synergism, and drug resistance reversal." Walker DM, Lazarova TI, Riesinger SW, Poirer MC, Messier T, Cunniff B, Walker VE. Frontiers in Oncology. 2023 Jul 28;13:1212604. doi: 10.3389/fonc.2023.1212604. PMID: 37576902; MPCID: PMC10419174. h-index: 113

"Structural and functional fine mapping of cysteines in mammalian glutaredoxin reveal their differential oxidation susceptibility." Corteselli EM, Sharafi M, Hondal R, MacPherson M, White S, Lam YW, Gold C, Manuel AM, van der Vliet A, Schneebeli ST, Anathy A, Li J, Janssen-Heininger YMW. Nature Communications. 2023 Jul 28;14(1):4550. doi:10.1038/s41467-023-39664-2. PMID: 37507364; PMCID: PMC10382592. h-index: 449

"Deletion of Miro1 in airway club cells potentiates allergic asthma phenotypes." Bruno S, Lamberty A, McCoy M, Mark Z, Daphtary N, Aliyeva M, Butnor K, Poynter ME, Anathy V, & Cunniff B. Frontiers in Allergy. 2023 4, 1187945. https://doi.org/10.3389/falgy.2023.1187945. H-Index: 4

"Diagnosing calciphylaxis: A series of cases with both imaging and tissue biopsy." Alniemi DT, Kanner C, Stowman AM, Knapp M, McGevna L, Seward DJ, Bui MR. Journal of the American Academy of Dermatology. 2023 May;88(5):1117-1119. doi: 10.1016/j.jaad.2020.05.111. Epub 2020 Jun 8. PMID: 32526323

Corrigendum to "Spatiotemporal higher-order chromatin landscape of human histone gene clusters at Histone Locus Bodies during the cell cycle in breast cancer progression." Ghule PN, Boyd JR, Kabala F, Fritz AJ, Bouffard NA, Gao C, Bright K, Macfarlane J, Seward DJ, Pegraro G, Misteli T, Lian JB, Frietze S, Stein JL, van Wijnen AJ, & Stein GS. [Gene 872 (2023)147441]. Gene 873, 147469 Advance online publication. https://doi.org/10.1016/j.gene.2023.147469

"Spatiotemporal higher-order chromatin landscape of human histone gene clusters at Histone Locus Bodies during the cell cycle in breast cancer progression." Ghule PN, Boyd JR, Kabala F, Fritz AJ, Bouffard NA, Gao C, Bright K, Macfarlane J, Seward DJ, Pegraro G, Misteli T, Lian JB, Frietze S, Stein JL, van Wijnen AJ, & Stein GS. Gene,147441. 2023 Advance online publication. https://doi.org/10.1016/j.gene.2023.147441

"Addressing the Environmental Impact of Science Through a More Rigorous, Reproducible, and Sustainable Conduct of Research." Meyn SM, Ramirez-Aguilar KA, Gregory CW, Mische S, Ott AW, Sol-Church K, Sturges M, Taatjes DJ. Journal of Biomolecular Techniques. 2023 Feb 28;33(4):3fc1f5fe.d085ce95. doi: 10.7171/3fc1f5fe.d085ce95. PMID: 37033093; PMCID:10078834

"Rigor, Reproducibility, and Transparency in Shared Research Resources: Follow-up Survey and Recommendations for Improvement." Journal of Biomolecular Techniques. Ott AW, Sol-Church K, Deshpande GM, Knudtson KL, Meyn SM, Mische SM, Taatjes DJ, Sturges MR, Gregory CW. 2022 Aug 16;33(3):3fc1f5fe.fa789303. doi: 10.7171/3fc1f5fe/fa789303. PMID: 36910580; PMCID: PMC10001929

"Novel post-acquisition image processing to attenuate red blood cell autofluorescence for quantitative image analysis." Epub ahead of print. Bouffard NA, Lee K, DeLance NM, Clason T, Chatterjee N, Taatjes DJ. 2022 Oct 19. doi: 10.1007/s00418-022-02159-0. PMID: 36260111

"Differences in Treatment Response in Bronchial Epithelial Cells from Idiopathic Pulmonary Fibrosis (IPF) Patients: A First Step towards Personalized Medicine?." Antioxidants (Basel). Veith C, Schneider MA, Maas L, van der Vliet A, van Schooten FJ, Kreuter M, Meister M, Boots AW, Kahn N. 2023 Feb 10;12(2):443. doi: 10.3390/antiox12020443. PMID: 36830000; PMCID: PMC9952618

"Diet-Induced Obesity Worsens Allergen-Induced Type 2/Type 17 Inflammation Ain Airways by Enhancing DUOX1 Activation." Habibovic A, Hristova M, Morris CR, Lin MJ, Cruz LC, Ather JL, Geizst M, Anathy, V, Janssen-Heininger YMW, Poynter ME, Dixon AE, van der Vliet A. 2023 Jan 10. doi: 10.1152/ajplung.00331.2022. Epub ahead of print. PMID: 36625485

"In Focus in HCB." Taatjes DJ, Roth J. Histochemistry Cell Biology. 2023 Jan 9:1-3. doi: 10.1007/s00418-022-02176-z. Epub ahead of print. PMID: 36622387; PMCID: PMC9827435

"Mitoquinone mesylate attenuates pathologic features of lean and obese allergic asthma in mice." Chandrasekaran R, Bruno SR, Mark ZF, Walzer J, Caffry S, Gold C, Kumar A, Chamberlain N, Butzirus IM, Morris CR, Daphtary N, Aliyeva M, Lam YM, van der Vliet A, Janssen-Heininger Y, Poynter ME, Dixon AE, Anathy V. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2022 Dec 13. doi: 10.1152/ajplung.00249.2022. Epub ahead of print. PMID: 365151

A recent editorial from Vikas Anathy. Editorial: "Oxidative stress related to cellular metabolism in lung health and diseases." Arunachalam K, Anand K, Palanisamy S, Anathy V. Frontiers in Pharmacology 2022 Nov 3;13:1015423. doi: 10.3389/fphar.2022.1015423. PMID: 36408268; PMCID: PMC9670798