Cellular Stress Response Research Shows Promise for Conditions Affecting Warfighters

Ambar Rodriguez-Martinez, M.S., research associate, studies disease-causing patient mutations that inappropriately activate the cellular stress response. (Photo credit: Tom Balfour, USU)

By Vivian Mason

No matter who you are, your cells experience a wide variety of environmental stresses on a daily basis. These stressors could be as severe as an exposure to toxins, or something as commonplace as ultraviolet (UV) damage from the sun. In the Young-Baird research laboratory at the Uniformed Services University (USU), researchers, headed by principal investigator Dr. Sara Young-Baird, assistant professor in the Department of Biochemistry and Molecular Biology (BIO) at USU’s School of Medicine (SOM), are studying how our cells respond to stress, and how their findings can be applied to complex conditions – specifically those that affect our military service members.

Sara Young-Baird, Ph.D., assistant professor at USU's BIO department, joined the University in 2022. Her research program focuses on understanding mechanisms of protein synthesis regulation in the context of cellular stress and  human disease. (Photo credit: Tom Balfour, USU)
Sara Young-Baird, Ph.D., assistant professor at USU's BIO
department, joined the University in 2022. Her research
program focuses on understanding mechanisms of protein
synthesis regulation in the context of cellular stress and 
human disease. (Photo credit: Tom Balfour, USU)
“A cellular stress response pathway called the integrated stress response is at the core of my research program,” Young-Baird says. “The integrated stress response is a molecular signaling pathway that helps our cells acclimate to changes in the environment and maintains overall cell health.” 

Impaired or inappropriate activation of this cellular stress response pathway is a common underlying factor for many human diseases, including those that affect our military warfighters and veterans, such as traumatic brain injury, posttraumatic stress disorder, various cancers, and diabetes.

Maintenance of cell health and function is essential for prevention of human disease. When our cells experience stress, they can respond in a variety of ways, ranging from activation of pathways that promote cell survival to eliciting programmed cell death that eliminates damaged cells. “These cell fate decisions,” explains Young-Baird, “are driven at least partially through the regulation of protein synthesis.”

The Young-Baird lab studies protein synthesis, which is the process by which RNA is decoded or ‘translated’ into proteins. “These proteins are the biological molecules that carry out most cellular functions,” says Young-Baird.  They provide structure to cells, determine cell shape and function, and serve as enzymes to break down food for energy. 

While our DNA encodes many proteins, not all proteins are produced in equal amounts or at the same time. During activation of the integrated stress response, for instance, specific proteins are made that clean up or repair damage from environmental insults. Since the tight regulation of protein synthesis is integral to all cellular and, therefore, human health, Young-Baird feels that “a better understanding of this fundamental process and its role in cellular stress alleviation has far-reaching implications in the biomedical field.”

In addition to their mechanistic work on the integrated stress response, the Young-Baird lab also studies how genetic mutations in the protein synthesis machinery drive human disease. 

The lab―currently consisting of molecular and cell biology predoctoral student, Anthony Erb, and research associate, Ambar Rodriguez-Martinez―recently found that the process of protein synthesis is dysregulated in a severe neurological disorder called MEHMO (Mental or intellectual disability, Epileptic seizures, Hypogenitalism, Microcephaly, and Obesity) syndrome.

MEHMO syndrome is a genetic disease that commonly shows symptoms prenatally or within the first 24 months after birth. MEHMO can result in mild to profound intellectual disability, epilepsy, obesity, early-onset diabetes, growth decay, microcephaly, and hypogenitalism. 

The genetic disease is caused by mutations in an essential component of the protein synthesis machinery. The resulting dysregulation in protein synthesis leads to elevated production of cellular stress response proteins and activation of the integrated stress response, even in the absence of a cellular stress potentially underlying the disease symptoms.

“One can think of cellular protein synthesis levels like the Goldilocks fairy tale,” says Young-Baird. “Production of too little or too much protein can impair cell function. For a cell to be healthy, the right proteins need to be generated at the right time and at the right level.”

The lab uses many different model systems to address core research questions, including mammalian cell lines and yeast, which are commonly used to study human genetics. 

“In our recent work on MEHMO syndrome,” says Young-Baird, “we used patient-derived induced pluripotent stem cells (iPSCs) to investigate the molecular basis of the disease. iPSCs are really unique because they can be derived from adult skin cells and are capable of being differentiated (or transformed) into various other cell types. Since many MEHMO patient symptoms are neurological in nature, we differentiated the iPSCs into neurons and found that the patient mutation severely impacted their health and function.” 

Anthony Erb, Molecular and Cell Biology Department graduate student, is exploring novel molecular mechanisms of protein synthesis regulation during cellular stress. Anthony Erb, Molecular and Cell Biology Department graduate student, is exploring novel molecular mechanisms of protein synthesis regulation during cellular stress. (Photo credit: Tom Balfour, USU)
Anthony Erb, Molecular and Cell Biology Department graduate student, is exploring novel molecular mechanisms of protein synthesis regulation during cellular stress.
(Photo credit: Tom Balfour, USU)

During the course of this work, the Young-Baird lab identified a drug, called ISRIB (Integrated Stress Response Inhibitor) that appears to be a good therapeutic candidate for the disease. Treatment of the iPSCs and neurons with this compound suppressed both the protein synthesis and neuronal differentiation defects associated with the MEHMO patient mutation. 

“The next step in our assessment of ISRIB’s therapeutic potential,” Young-Baird says, “will be testing the effect of ISRIB treatment in a mouse model of MEHMO syndrome.”

Though MEHMO syndrome is estimated to affect fewer than 1,000 Americans, the Young-Baird lab’s research to understand the molecular cause of the disease and gain a better grasp of its processes could allow better insight to other genetic diseases on a cellular level.

“Studying how a process has been disrupted in a disease setting can also clarify how the process works whenever conditions are favorable,” Young-Baird explains. “In the long term, our goal is to be able to apply our findings to other complex conditions where cell health may be jeopardized, particularly focusing on those that affect our military warfighters.”

In helping to achieve that goal, Young-Baird says that she’s grateful for the generous support she’s received from her colleagues at USU.

“The supportive environment here was a big factor in my decision to join the USU team,” she concludes. “It was obvious very early on in my interview process that the USU family is a close-knit group of colleagues that work together to conduct cutting-edge research and educate our future military health professionals, scientists, and leaders.”