Please describe the research questions of your lab.
Several acute and chronic lung diseases result from ineffective regeneration of the alveolar epithelium after injury. We have no therapeutic options to promote regeneration, in part because of our limited understanding of the underlying mechanisms. The alveolar epithelium consists of type 1 and type 2 alveolar epithelial cells (AECs). AEC1s play a critical role in barrier function since they cover >95% of the alveolar surface and facilitate efficient gas exchange by virtue of their exquisitely thin morphology. However, AEC1s are highly susceptible to death during lung injury due to a variety of insults. Surviving AEC2s are the principal progenitor responsible for regenerating the injured alveolar epithelium. AEC2s proliferate to replace lost cells, then differentiate into AEC1s to restore normal alveolar architecture and function. Impaired regeneration results in lung disease, including pulmonary fibrosis. We have identified mechanisms underlying AEC2 proliferation, including β-catenin signaling (1) and AEC2-to-AEC1 differentiation, including a novel AEC2-AEC1 transitional cell state that emerges transiently during normal regeneration (2) but persists in pulmonary fibrosis (3). We also study the role of immune cells in causing lung injury and both promoting physiologic regeneration and impairing regeneration during disease pathogenesis. We hope these findings may eventually lead to novel therapies to promote normal regeneration and ameliorate lung disease.
What genetics/genomics techniques do you utilize in your lab?
We have taken advantage of genomics techniques to identify key mechanisms of alveolar injury and regeneration. A decade ago, we used a microarray to identify β-catenin as a key signal regulating AEC2 proliferation (1). More recently, we used single cell RNA sequencing (scRNAseq) to identify novel transitional states that arise during AEC2-to-AEC1 differentiation and TGFβ as a checkpoint regulating these transitional states [(2), https://rnabioco.github.io/lung-scrna/?ds=lung_regeneration_lps_model]. As these novel states were likely only discernible via scRNAseq technology, it has become increasingly clear to me that the major advances in our field have and will continue to emerge as a direct result of major advances in genomics technologies.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question.
We use genomics techniques such as RNAseq to identify candidate signaling pathways that regulate alveolar injury and regeneration, lineage tracing to study regeneration, gene deficient mice to test the function of these signaling pathways, and in vitro systems to further dissect mechanism.
At what point in your life did you decide you wanted to be a scientist/physician?
During high school biology, I realized I wanted to do bench science but ultimately decided to go to medical school because I thought it would help me ask clinically relevant questions.
In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?
In the field of pulmonary fibrosis, there was the identification of mutations in surfactant proteins, telomerase, and MUC5b that cause or predispose to disease. And there are many other examples in asthma, COPD, etc.
Briefly describe your favorite publication involving genomics/omics that you were involved with in general-audience terms.
Well, I of course have to mention the alveolar epithelial transitional state that was first identified in our laboratory by scRNAseq to arise transiently in mice during normal regeneration (2). We subsequently found that this state persists in pulmonary fibrosis (3). These findings were very exciting to me for several reasons: First, they were subsequently validated by other groups (4) (5) (6) (7) (8) (9). Second, this work revealed that the cellular and molecular mechanisms of regeneration are conserved regardless of the initial cause of injury, a seminal finding with important clinical implications. Finally, this work underscores that that basic research into mechanisms of normal biology (physiologic regeneration) can stimulate novel hypotheses about disease pathogenesis. What will ultimately be most satisfying is if and when these findings are translated into novel therapies for this devastating disease.
What is your favorite aspect of ATS?
It’s hard to name just one, but the highlight for everyone is the International Meeting. Although it unfortunately was held in virtual format this year, the scientific sessions were no less outstanding and provocative. I value tremendously the collaborations that have arisen from the Meeting, participating in RCMB, AII, and now the Genomics Assembly, and of course the opportunity to see old friends once a year.
How could your research assist scientists and clinicians in other assemblies at ATS?
I am very fortunate to have established many productive collaborations. Although these skills are not unique to my lab, I am happy to help with mouse models of lung injury, alveolar epithelial cell isolation and culture, lineage tracing, immunostaining/fluorescent in situ hybridization, and scRNAseq study design and interpretation.
Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?
Absolutely! Our newly acquired proficiency with virtual communication will make national and international collaborations even more productive and fun. I am always looking to hire at all levels and at the moment am particularly interested in an enthusiastic postdoc. Please apply here.
Please include your email address or lab website to share with potential collaborators!
Email: zemansr@med.umich.edu
Website: https://sites.google.com/view/rachelzemanslab/
Twitter: @RachelZemans
