August 28, 2014

Ascano seeks to shed light on cellular stress response

Ebola. Chikungunya. Influenza. What’s to be done about these headline-grabbing, debilitating, often lethal viruses?

Manuel Ascano is studying the cellular stress response for insights into improving the treatment and prevention of viral infections. (photo by Daniel Dubois)

Ebola. Chikungunya. Influenza. What’s to be done about these headline-grabbing, debilitating, often lethal viruses?

Turns out the cell has ways to repel viral invaders. These defense mechanisms not only can ward off external attacks but also threats from within the body, including autoimmune disorders.

If we knew better the cell’s innate immune system and how it responds more generally to “cellular stress,” we might be able to improve treatment and prevention of viral infections, and we also might discover new treatments for neurological disorders, cancer and other diseases.

That’s the goal of Manuel Ascano, Ph.D., recruited this summer from New York’s Rockefeller University to his first faculty position at Vanderbilt. His aim — to advance understanding of post-transcriptional gene regulation, how proteins interacting with RNA and DNA enable cells to rapidly adjust to changes in their environment.

“In the end, it’s really a war in gene expression, isn’t it?” said Ascano, assistant professor of Biochemistry and of Pathology, Microbiology and Immunology. “Who gets to use what in a cell?”

Many viruses, for example, hijack the cell’s transcriptional and translational “machinery” to reproduce.

“The cell needs to very rapidly stop things that (can cause damage) from being made into protein, and at the same time … turn on genes that are involved in the stress response to make sure the cell gets back into some sort of normalcy,” he said.

The cellular stress response is like a finely tuned, massive orchestra. Hundreds if not thousands of “binding proteins” regulate RNA and DNA expression by binding to the nucleic acids. Other proteins “sense” the presence of foreign DNA outside the nucleus, in the cytoplasm, where it is not supposed to be.

One member of this early warning system is STING, for STimulator of INterferon Genes. Interferons are proteins that are secreted out of one cell and can stimulate neighboring cells to activate their anti-viral and pro-inflammatory genes.

These and other sensor pathways also activate RNA- and DNA-binding proteins, and they ultimately regulate what gets expressed in the cell. This, in essence, is how the cell puts itself on “alert,” Ascano said.

Inflammation is a classic response of cells to stress. The molecular components that promote inflammation are actually shared across many triggers of stress, and several have been implicated in the etiology of heart disease and cancers.

Cellular stress also may play a role in late-onset neurological disorders. Ascano is investigating its role in fragile X syndrome, the most common inherited form of intellectual disability.

A native of the Philippines, he came to the United States with his parents, both physicians, when he was 2.

During his senior year of high school in Princeton, Illinois, the teacher of his Advanced Biology laboratory class taught students how to isolate DNA from a calf thymus. Ascano was hooked. “I said, ‘Yeah, I need to do this,” he said.

Ascano, 38, majored in Microbiology at the University of Illinois at Urbana-Champaign, where he met his wife Janice, also a scientist who currently works for an international non-profit neurological research foundation. They have two children.

He went on to earn his doctorate in Biochemistry at the University of Cincinnati College of Medicine, and then got a postdoctoral fellowship at Rockefeller in the laboratory of RNA silencing pioneer Thomas Tuschl, Ph.D.

Ascano said he chose to come to Vanderbilt largely because of its diversity of research and strength in proteomics.

“I’m interested in the transition from RNA to protein,” he said. “Here was a place that is developing novel tools that can complement my research program and is an emerging need in my field.”

At Vanderbilt, he said, “I can put a unique spin on my work.”