LCOM & Department News

van der Vliet's Study Finds Potential New Treatment Target for Obesity-Associated Asthma

April 19, 2023 by Jennifer Nachbur

A new study in the American Journal of Physiology-Lung Cellular and Molecular Physiology by Albert van der Vliet, Ph.D., professor of pathology and laboratory medicine, and colleagues is honing in on why people with asthma often have worse symptoms if they are obese.

Albert van der Vliet, Ph.D. (left), and Aida Habibovic in van der Vliet's lab at the University of Vermont's Larner College of Medicine.

A 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. 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.
According to the U.S. Centers for Disease Control and Prevention, obesity “is associated significantly with the development of asthma, worsening asthma symptoms, and poor asthma control.” Research by the American Lung Association has found that people with a body mass index (BMI) in the obese range do not respond in the same way to asthma medications as people with a lower BMI. Nonetheless, say the authors of this new study, “the mechanisms by which obesity leads to worsened asthma symptoms still remain poorly understood.”
 
This new research demonstrates that the gene DUOX1 likely contributes to the connection between obesity and asthma.
 
DUOX1 encodes for Dual oxidase 1, an enzyme that converts oxygen to reactive oxygen species, such as hydrogen peroxide. Reactive oxygen species are thought to be damaging to cells because they can oxidize many important biomolecules. They are also generated intentionally, however, by specific enzymes called NADPH oxidase, which reside in inflammatory cells, due to their ability to help kill pathogenic bacteria. For example, DUOX1 is a specific form of NADPH oxidase, which is primarily present in epithelial cells that line mucosal surfaces, such as in the respiratory tract, and has host defense functions similar to that of other NADPH oxidases in inflammatory cells.
 
Past research by van der Vliet and others has demonstrated that DUOX1 also plays an important role in maintaining epithelial integrity by mediating innate wound responses to various forms of environmentally induced injury. This is not simply due to cytotoxic effects of reactive oxygen species, but rather by controlled production of hydrogen peroxide, which can then activate redox-based cellular signaling mechanisms that regulate cell migration or production of proinflammatory cytokines or genes involved in wound repair processes.
 
Van der Vliet, who with former graduate students David Heppner, Ph.D., and Karamatullah Danyal, M.D., Ph.D., was awarded a patent for “Covalent inhibitors of dual oxidase 1 (DUOX 1)” in 2018, has been conducting research in this field for more than two decades. He and his colleagues have previously demonstrated an important role for DUOX1 in maintaining epithelial integrity and in innate allergic responses. In addition, his lab has found that alterations in DUOX1 expression have been associated with such chronic diseases as asthma, COPD, and lung cancer. 
 
“Our findings may offer further justification of implicating DUOX1 as an appropriate alternative therapeutic target, particularly in cases of obesity-associated asthma in which other treatment strategies have proven ineffective,” the study’s authors say. 
 
To assess the role of DUOX1 in obesity-related asthma, the research team looked at a combination of human, animal, and in vitro studies, and collected human nasal samples from obese and non-obese participants with allergen-induced asthma before and after exposure to an irritant. In mice, they compared unmodified mice, mice that do not produce DUOX1 at all, and mice in which DUOX1 can be selectively turned off. Mice were fed either a high- or low-fat diet. After 14 weeks of feeding, mice were exposed either to an irritant to induce an allergic response or to a saline control. The research team then analyzed a variety of their tissues. In a separate study, mice were repeatedly exposed to the irritant to induce a model of chronic exposure.  
 
In humans, statistical analysis “revealed a significant positive association” between body mass index and markers of DUOX1 activity. Multiple markers of DUOX1 activity and of inflammation were higher in the participants with asthma compared to controls and still higher in the participants with both asthma and obesity. The mouse and in vitro studies further verified these findings. Obese mice showed greater DUOX1 activity. When DUOX1 was not present, many of the inflammatory markers seen in asthmatic reactions were either not present or significantly reduced even in obese animals. 
 
“Increased epithelial expression and activation of DUOX1 represents an important factor in [allergic inflammation in the context of diet-induced obesity],” conclude the authors. In addition to van der Vliet, who is senior author on the paper, coauthors include Aida Habibovic, lab research technician in pathology and laboratory medicine; Milena Hristova, temporary lab research technician in pathology and laboratory medicine; Carolyn Morris, Ph.D., faculty scientist in medicine; Miao-Chong Joy Lin, Ph.D., faculty scientist in medicine; Litiele Cruz, Ph.D., visiting scholar in pathology and laboratory medicine; Jennifer Ather, senior lab research technician in pathology and laboratory medicine; Miklós Geiszt, M.D., Ph.D., Semmelweis University, Hungary; Vikas Anathy, Ph.D., associate professor of pathology and laboratory medicine; University Distinguished Professor of Pathology and Laboratory Medicine Yvonne Janssen-Heininger, Ph.D.; Matthew Poynter, Ph.D., professor of pathology and laboratory medicine; and Anne Dixon, M.A., B.M.B.Ch., professor and interim chair of medicine. 

(This article was adapted with permission from a press release produced by the American Physiological Society.)

 

Past Department Highlights

Mark_FungCongratulations to Dr. Mark Fung, M.D., PhD., Professor Pathology and Laboratory Medicine, on receiving the 2023 College of American Pathologists (CAP) Lifetime Achievement Award. Dr. Fung is a nationally recognized expert in transfusion medicine. (10/2023) 

Congratulations to Jessica Crothers, M.D., Assistant Professor Pathology and Laboratory Medicine, on achieving the Notice of Special Interest Team Science award from NIAID for: "Effects of the gut microbiota on oral vaccine response in adults and children." (10/2023)

Nicole BouffardCongratulations to Nicole Bouffard on being awarded the "Scientific Research Staff Award" for 2023. This was presented to Nicole at the September 21, 2023, LCOM Research Excellence Award Ceremony. This is a great honor for Nicole and the Department of Pathology and recognizes her contributions and importance to the department and MIC. (10/2023)

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. (9/2023)

Congratulations to Yvonne Janssen-Heininger, Ph.D., Professor Pathology and Laboratory Medicine, on becoming a University of Vermont Cancer Center Program Co-Leader, Cancer Cell. (9/2023)

Congratulations to the following pathology members on receiving research support funds in April 2023. Recipients were: John Kennedy, M.D., $6520 for morphologic and immunohistochemical re-evaluation of renal cell carcinomas exhibiting papillary architecture, with emphasis on tumors demonstrating "type 2" morphology. 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)

Congratulations to the following faculty members on their promotions: Vikas Anathy, Ph.D., to Professor with tenure, Bronwyn Bryant, M.D., to Associate Professor, John DeWitt, M.D., Ph.D., to Associate Professor, Sarah Nowak Ph.D., to Associate Professor, and Christi Wojewoda, M.D., to Professor. (6/2023)

Bei Zhang, M.D., M.S., Ph.D., MLS(ASCP), associate professor of pathology and laboratory medicine, did an educational scholarship session titled "Activate Students Learning Outside Classroom." at the 8th International meeting of the Association of Biochemistry Educators. Dr. Zhang also conducted two additional workshops with other ABE members titled "Linking Clinical Presentations to Their Biochemistry: A novel ABE Clinical-Biochemistry Curricular Treat Mapping Educational Tool.", and "Getting to Clerkship and Beyond: Crafting Biochemistry Learning Objectives that Connect and Integrate Basic Science Concepts with Clinical Application." (5/2023)

Congratulations to Dr. Maureen Harmon, M.D., associate professor of pathology and laboratory medicine, and Dr. Amer Abu Alfa, M.D., assistant professor of pathology and laboratory medicine for being recognized by medical students for their professionalism. Dr. Harmon was recognized for social responsibility and Dr. Abu Alfa was recognized for compassion. (5/2023)

Congratulations to Mary Cushman, Ph.D., M.Sc., professor of medicine and pathology and laboratory medicine, on being named a University Distinguished Professor of Medicine, Hematology/Oncology Division, and Pathology and Laboratory Medicine. (5/2023)

View the story Mammograms of a study by Sarah Nowak, Ph.D., assistant professor of pathology and laboratory medicine, and researchers at the UVM Cancer Center showing data that fewer women being screened for breast cancer. (4/2023)

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 Bronwyn Bryant, M.D., Assistant Professor of Pathology and Laboratory Medicine, for having your proposal, Consequential Validity of Entrustable Professional Activities in Pathology Residency Training selected to receive a Frymoyer Scholars Program project of $48,000 to be funded July 1, 2023 through June 30, 2025. (4/2023)

Congratulations to Martin Chang, M.D., Ph.D., on accepting the new role as Vice Chair for Faculty Affairs. (4/2023)

Congratulations to Joanna Conant, M.D., on becoming the new Pathology Student Fellowship Director starting July 1, 2023. (4/2023)

Congratulations to The Cunniff Lab, on receiving funding to support research focused on malignant mesothelioma. The funding was from The Butler Family Foundation Fund for Cancer Research at the University of Vermont Cancer Center. The Butler Fund was established by the Butler family in memory of two loved ones lost to mesothelioma. (03/2023)

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)

A number of faculty and students from the pathology and laboratory medicine department presented research at the American Heart Associations Epidemiology, Prevention, Lifestyle, and Cardiometabolic Health (EPI/Lifestyle) Scientific Sessions 2023 in Boston February 28 - March 3. Students presenting were Maggie King, a master in science pathology degree student who was mentored by faculty scientist J. Peter Durda, Ph.D. pathology and laboratory medicine.  Maggie presented on "Complete Blood Count Analysis in the Risk Underlying Rural Areas Longitudinal (RURAL) Cohort Study with a Point of Care Instrument." Her study is supported by NHLBI. And second-year medical student and 2022 Cardiovascular Research Institute Summer Research Fellow Megan Zhou, mentored by pathology and laboratory medicine associate professor Nels Olson, Ph.D. Megan presented on  "Coagulation Factor IX and Incident Diabetes Risk: The Reasons for Geographic and Race Differences in Stroke (REGARDS) Study." Also, pathology and laboratory faculty members that were coauthors of presentations given, assistant professor Margaret Doyle, Ph.D., and University Distinguished Professor of pathology and laboratory medicine, Russell Tracy, Ph.D. (3/2023)

Congratulations to Dr. Bei Zhang, M.D., Ph.D., MLS(ASCP), associate professor of pathology and laboratory medicine, for being selected for a Distinguished Scholar Award by the Association of Biochemistry Educators for her submission entitled "Activate Students' Learning Outside Classroom". Dr. Zhang will be presenting this submission at the 2023 Association of Biochemistry Education Conference. (3/2023)

Congratulations to our 2023 Gender Equity Award Nominees. Gender Equity Champion Award nominee, Debra Leonard, M.D., Ph.D., Chair and Professor Pathology and Laboratory Medicine. Our departmental nominees for The Polaris Award for Outstanding Mentorship- an award for informal or formal mentorship for women or gender diverse college community members, Rebecca Wilcox, M.D., Pam Gibson, M.D., Yvonne Janssen-Heininger, Ph.D., and Christi Wojewoda, M.D. (2/2023)  

Congratulations to Dr. Scott Anderson, M.D., on being selected to receive the Association of Pathology Chairs 2023 Margaret Grimes Distinguished Achievement Award in Graduate Medical Education. This award was made in recognition of Dr. Anderson's outstanding contributions to graduate medical education and his stature as a nationally recognized leader in pathology education. (2/2023)

Congratulations to Dr. Yvonne Janssen-Heininger, Ph.D., Dr. Kelly Butnor, M.D., Dr. David "Bebo" Seward, M.D., Ph.D., and Dr. Sharon Mount, M.D., on their news story in The Charlotte News, on their "giant steps in cancer research." Read the full article here:   Humble Superstar (1/2023)

Congratulations to Dr. Elizabeth Bundock, M.D., Ph.D., Chief Medical Examiner of Vermont and clinical assistant professor of pathology, for her appointment by the American Board of Pathology, to the Test Development and Advisory Committee for Forensic Pathology 2023. (1/2023)

Dr. Beri Zhang, M.D., Ph.D., MLS(ASCP), associate professor of pathology and laboratory medicine, presented a panel, at the Snow Season Education Retreat, titled "The Pearls and Pitfalls of Publishing in Medical Education", with three clinicians Dr. Hale, Dr. Halle, and Dr. Rideout. (1/2023)

Congratulations to Dr. Bronwyn Bryant, M.D., assistant professor of pathology and laboratory medicine on her Awards for  Teaching and Educational Excellence, Learner Assessment, conferred at the Teaching Academy Induction and Award Ceremony on January 11, 2023. (1/2023)