Assistant professor Sam Fagg, MS, PhD, uses lab-grown human cells to study how a protein called Quaking exerts its influence over development and disease. Recently, Dr. Fagg, who works in the Transplant Division of the Department of Surgery at the University of Texas Medical Branch (UTMB), received a $2 million R35 award from the National Institutes of Health to support his work. He says his time as a KL2 Scholar in the mentored career development program offered by UTMB’s Institute for Translational Sciences (ITS) was critical to obtaining this prestigious funding.
As a KL2 Scholar, Dr. Fagg used heart cells created from human stem cells to study how Quaking regulates gene expression. Quaking is an RNA-binding protein, which is an under-studied type of gene regulator that holds significant promise for modern drug design. Through its ability to regulate the activity of a variety of genes, Quaking influences how the heart and other body parts develop. When disrupted, Quaking may also be a culprit in heart disease and other serious conditions. In his KL2 project, he and his team engineered the stem cell-derived heart cells to replicate heart attack conditions and examined the complex and dynamic molecular network in which Quaking operates. This work provides a first step toward designing novel medicines that could reduce scar tissue formation and other damage after a heart attack. In addition, Dr. Fagg’s KL2 studies underscored significant gaps in our understanding of how Quaking and other RNA binding proteins regulate gene activity.
Addressing those gaps is the goal of his R35 funding, which also marks Dr. Fagg’s successful transition from KL2 Scholar to independent researcher. The ITS KL2 program, funded by a Clinical and Translational Science Award from the National Center for Advancing Translational Science, helps early career scientists become independently funded investigators through mentoring, didactic training, and financial support that enables Scholars to focus the majority of their time on research efforts. Dr. Fagg spoke with the ITS about the impact of the KL2 program on his career.
How did your experience as a KL2 Scholar impact your time developing this grant?
The KL2 absolutely was critical. We got quite a bit of work done on the project in the KL2 time period, and much of that data fed into the R35 application. Before I got the KL2, my salary was supported by a research endowment to the Transplant Research group. The KL2 freed up money so that we were able to hire a talented post doc Karen Pereira de Castro, MSc, PhD, to work on the project. These things all lead to more good things, and now I also have Brian Amburn, a MD-PhD student, working on that project.
In my KL2 project, I examined the molecular mechanisms through which a potential disease process is mediated. By studying the molecular mechanisms in a disease context, I was able to turn that work into fundamental biology-based grant proposal. In order to make those discoveries, I had to use models relevant to human development and disease.
What were other important features of the KL2 program?
The structure of the general program is definitely helpful, especially the monthly meetings of all of the KL2 Scholars and a panel of mentors. It’s basically a monthly check in and it’s never anything intimidating or nerve-racking. It really facilitates open and honest discussion. I was never worried that I don’t have anything to say. I would walk in there and find support from a friendly sounding board of people with diverse backgrounds who can advise on a lot of different topics--everything from fundamental biologists to MDs that only do clinical research.
What did you propose in your R35 application, and how could this help patients?
The grant is structured toward the fundamental molecular mechanisms of RNA-binding proteins. One of the things we proposed to do in the R35 is to examine how Quaking interacts with another gene-regulating entity that is an RNA and has been implicated in myocardial infarctions, more commonly known as heart attacks. One region of this RNA is enriched for Quaking binding sites and we think that when Quaking binds to it then the function of one or the other (or both) are blocked. The model we have proposed is that around the time of a heart attack or heart disease, this RNA is activated and its levels go up, and Quaking is sponged up and can’t do its normal job. We can use our stem cell systems and in vitro systems to determine if that is indeed a pathway that generates a pathological response, and if so, it becomes a druggable target. I can imagine a synthetic RNA that you could give to a patient that would then mask the Quaking binding sites on this other RNA, so that even when its levels go up during and after a heart attack, Quaking does not get stuck. Without the KL2, I would not have had the support to be able to uncover this interesting interaction that could lead to fundamental discoveries about gene regulation and potentially a new therapeutic modality for heart disease.