Jacob, Kotton, and colleagues have developed a method for producing self-renewing lung alveolar epithelial cells from any patient. Their protocol, published in the December 2019 issue of Nature Protocols follows on their recent Cell Stem Cell publication (Jacob et al. Cell Stem Cell, 2017) where the team was able to reprogram patient blood specimens into induced pluripotent stem cells and then discovered how to employ these stem cells to engineer new human lung epithelial cells in the laboratory. Anjali Jacob, the first author of the new publication, developed the method as part of her doctoral thesis work as a BU MD/PhD student in the Pulmonary Center and Center for Regenerative Medicine. Induced pluripotent stem cells (iPSCs) are the engineered equivalent of embryonic stem cells, but can be generated from adult patients through a technology known as reprogramming. The Kotton Laboratory is an international leader in applying reprogramming to generate lung disease-specific iPSCs for gene editing and disease modeling. The team has received numerous awards both for their discoveries of how to coax these cells into new lung cells in vitro as well as for the group’s willingness to share these cells, even ahead of publication, as open source reagents with the international research community. Kotton has been recognized for this work through the American Thoracic Society’s Research Achievement Award and through the American Association of Medical Colleges inaugural Research Resource Sharing Award.
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Several Pulmonary Center trainees got great news from the NIH on recent grant applications, including:
Pulmonary Fellow Nicholas Bosch, M.D.
Nick will be receiving an F32 award from the NIGMS titled "Normalizing vasopressor dose to standardize vasopressors practice in septic shock." This award will allow him, under the mentorship of Dr. Allan Walkey, to 1) develop and validate a normalized measure of vasoplegia that incorporates vasopressor dose to physiologic blood pressure response and 2) characterize and leverage practice pattern variation in vasopressor use to identify the optimal time to initiate a second vasopressor medication. The results of this work may help to standardize consensus definitions, identify patients most likely to benefit from treatments targeting vasoplegia, and improve vasopressor practices in septic shock.
Pulmonary Fellow Kari Gillmeyer, M.D.
Kari will be receiving an F32 award from the NHLBI titled "Determining disparities in treatment of pulmonary arterial hypertension nationally." This award will allow her, under the mentorship of Dr. Renda Weiner, to investigate the influences on treatment for pulmonary arterial hypertension (PAH), a severe disease of the pulmonary vasculature characterized by high symptom burden, significant healthcare utilization, and poor survival. By capitalizing on rich administrative data maintained through the largest integrated healthcare system in the US, she will explore patient- and facility-level drivers of treatment in the community, with a focus on identifying potential racial/ethnic or economic disparities in treatment rates of PAH. The results of her work will establish a foundation on which to build and implement effective strategies to improve treatment rates and mitigate health disparities for patients with PAH.
Ph.D. Student Adeline Matschulat
Addie will be receiving an F31 award from the NHLBI titled, "Defining molecular signals that influence airway basal cell renewal and growth." This award will allow her, under the mentorship of Dr. Bob Varelas, to investigate basal sells in the airways. These cells are the resident stem cells of the airway epithelium and understanding how they are regulated and maintained is important for understanding their aberrant growth in diseases, such as COPD, cystic fibrosis and cancer, as well as for developing novel methods for harnessing these cells for the purposes of regenerative medicine. Specifically, Addie will study how the Hippo pathway, an important pathway for regulating cell growth and cell fate decisions, and Hippo pathways effectors impact basal cell maintenance and growth in the airway epithelium.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are complex syndromes with three overlapping phases characterized by the reduction of pulmonary compliance, disruption of the epithelial and endothelial barrier, and recruitment of inflammatory cells into the alveoli. However, how lung cells communicate with each other remains unclear.
This work uncovers a novel mechanism and functional significance of epithelium-immune cell crosstalk in response to noxious stimuli. Dr. Jin’s group was able to demonstrate that lung epithelial cell-derived extracellular vesicles (EVs) serve as key “signal transmitters” between the epithelium and alveolar macrophages. EVs are lipid bilayer-enclosed nanoparticles that are naturally released from a cell. Moreover, they were able to identify that caveolin-1, a membranous protein, is responsible for sorting microRNAs into EVs. MicroRNAs are small, highly conserved non-coding RNAs that are critical to regulate innate immune responses.
This study, providing insights into pathophysiological functions of lung cell-derived EVs and new directions for developing diagnostic/therapeutic approaches to ARDS, is published in the Journal of Experimental Medicine.
Congratulations to Professor Jay Mizgerd for renewing his R01 award from the NIH titled "Lung-resident antibacterial heterotypic immunity." The new award is for 5 years, through June 2024, and will be used to discover mechanisms that localize and instruct the memory T cells in the lung tissue that provide effective protection against pneumonia.
Dr. Korkmaz, can you please tell us about the new award you received?
My work studying the acute response to lower respiratory infection was recently funded as an F32 postdoctoral fellowship by the National Heart, Lung and Blood Institute at the NIH. This provides me the opportunity to delve into the previously unknown role of the scavenger receptor, LOX-1, during pneumonia and in the lung in general. Using cell-type specific genetic manipulation and techniques such as flow cytometry and RNA-sequencing we will characterize how LOX-1 modulates lung inflammation during pneumonia, expanding on previous data using pharmacological inhibition of LOX-1. Furthermore, obtaining a postdoctoral scholarship will allow me to attend more conferences and workshops where I can make connections with interdisciplinary researchers to enhance my scientific and career endeavors.
This work demonstrated that B cells, which typically protect us against infection, function abnormally and promote interstitial lung disease in patients with common variable immunodeficiency (CVID). CVID is a primary immunodeficiency, a type of disorder where individuals have an immune system that does not function properly – causing infections and, for reasons not understood, also leading to “non-infectious” complications like interstitial lung disease. Dr. Maglione and colleagues were able to therapeutically target B cells and ameliorate the lung disease in all 11 patients they treated. Using this approach, they were able to spare the patients side effects of more broadly immunosuppressive therapies. Lastly, they were able to determine that a protein known as B cell activating factor, or BAFF, is an important driver of the dysregulated B cells that drive this lung disease through a specific interaction BAFF has with BAFF receptor. This disease pathway mediated by BAFF may be a useful target for therapeutic interventions in these patients.
Congratulations to PhD student Emad Arafa in Professor Jay Mizgerd’s group for receiving an F31 award from the NIH on “Pneumonia and alveolar macrophage resilience”
On February 1, 2019, Paul J. (PJ) Maglione, MD, PhD, joined the Pulmonary Center as Assistant Professor in the Section of Pulmonary, Allergy, Critical Care and Sleep Medicine
What is your educational background?
I attended elementary through high school in the Hudson Valley of New York near Peekskill, about a 45 minute train ride from Manhattan. I went to college at the University of Rochester where I majored in microbiology and had my first introduction to immunology research while also running on the varsity cross country team. I got my MD, PhD at the Albert Einstein College of Medicine in the Bronx, which was the hospital where I was born. Then I went to Mount Sinai in New York for internal medicine residency, allergy/immunology fellowship, and post-doctoral research in the laboratory of Charlotte Cunningham-Rundles.
What does your research focus on?
I am interested in studying human B cell biology through the lens of primary immunodeficiency. As a physician-scientist I also see patients and my clinical focus is on antibody deficiency, which dovetails well with my research focus. One of my more longstanding interests has been the mechanisms underlying non-infectious complications of the most prevalent form of symptomatic primary antibody deficiency, common variable immunodeficiency (CVID). My most recent work has focused upon the pathogenesis of the interstitial lung disease affecting CVID patients.
What are you most excited about in joining BUMC?
After my very first visit to BUMC I remember telling one of my friends that I had met the people that I wanted to work with. I truly feel like I am among many kindred spirits at BUMC. Everyone I have met at BUMC seems energetic and positive, which I find very motivating and exciting. I am also eager to learn from and collaborate with the experts in B cell repertoire analysis, pulmonary immunology, and regenerative medication that call BUMC home. I know my research will be elevated significantly by working at BUMC, which will be vital for me to make the next steps in my career. I also look forward to applying my medical experience in clinical immunology to the BUMC patient population and helping to establish a multidisciplinary center for the care of immunodeficient patients.