NIH Awards $2 Million to Study How Cells Vary in Stress Responses

The National Institutes of Health awarded Jeffrey Lewis, an associate professor of biological sciences at the U of A, $2 million to study how cells vary in their responses to stress.  

In his application, Lewis noted that "proper regulation of stress defenses is a feature of healthy cells and organisms, and defects in stress defense are connected to a number of human disorders." 

Lewis generally seeks to understand how cells adapt and even thrive in the face of environmental stresses, such as extreme heat or starvation, and is interested in both the function and regulation of stress defenses. His lab studies the coordination and logic of stress-responsive regulatory networks and how stress defense genes allow cells to maintain homeostasis. He is also interested in how natural variation shapes differences in how individuals perceive and respond to stress. 

Lewis uses yeast as a model organism because, as he explains, "it grows really fast, we can obtain billions of cells, and it has arguably the best genetic toolkit for gene editing and mapping." 

This proposal will take advantage of natural variation in stress signaling in yeast to explore why certain individuals are more susceptible or resilient to stress, with a focus on less well understood post-transcriptional and post-translational modes of regulation. Post-transcriptional refers to the period after DNA has been converted into RNA to make proteins. Post-translational refers to modifications that occur in proteins after they have been made by RNA. Each stage of development plays a role in stress response at the cellular level. One goal of the study will be to see how genetic variation may influence these responses for better or worse. 

"We have a bunch of different wild yeast strains in the lab, and some of them are super resistant to stress," Lewis said of his approach. "Some of them are super sensitive to stress. Think heat stress or nutritional stress, starvation, anything that they would encounter in their environment. Some individuals do better and some do worse. And with yeast, we can cross these strains like you would cross plants. But unlike plants, we can get back millions and millions of different individuals because yeast are a microbe, and it's really easy to generate millions of progeny." 

"We can take a sample of those individuals and isolate their DNA before stress," he continued, "And then we can expose them to stress and only the survivors that have inherited different versions of stress defense genes, for example, the protective versions of those genes, are the ones that will survive. And we can sequence those and compare them to everyone and see what versions of the genes are more prevalent after stress." 

Lewis recently coauthored a paper on how cells can undergo a protein modification known as acetylation in response to heat shock. People with heart disease also exhibit different acetylation patterns than those with healthy hearts, as do people suffering from Parkinson's disease and cancer. Lewis thinks if his lab can tease out what the acetylation patterns in yeast proteins are telling us about stress responses, it has the potential to tell us what is happening in humans, ideally paving the way for therapeutics. 

Ultimately, this work will help generate a better understanding of post-transcriptional and post-translational stress responses, while clarifying why individual cells with certain genetic backgrounds are more resilient or more sensitive to stress. 

The award is what is known as an R35 or Maximizing Investigators' Research Award, which is an investigator-focused award sponsored by the National Institute of General Medical Sciences (or NIGMS). The award is not contingent on meeting a specific project goal but rather provides five years of funding to Lewis' lab to support all of his research program that falls within the mission of NIGMS, wherever it may lead. As such, it is a strong validation of the basic biomedical research being done by the Lewis Laboratory. 

The funds will largely be used to employ additional research staff and graduate students, as well as pay for access to specialized equipment needed for the study of proteomics and genomics.