After a heart attack or stroke, vital organs don鈥檛 receive enough oxygen. While restoring oxygen is vital, it can also hinder recovery by depriving cells of the energy needed to heal, increasing the risk of organ failure over time.
To better understand these detrimental conditions after heart attack and stroke, University of Maine Ph.D. candidate Alyssa Castle has recapitulated them in Caenorhabditis elegans, a microscopic, transparent roundworm commonly known as a nematode.
To support her research, the National Heart, Lung, and Blood Institute of the National Institutes of Health has awarded Castle a Predoctoral Individual National Research Service Award, known as an F31 fellowship. The competitive award supports promising doctoral students pursuing careers in biomedical research.
鈥媁orking with Suzanne Angeli, assistant professor of molecular and cellular biology, Castle is studying the type of mitochondrial dysfunction that occurs during aging and after age-related diseases such as heart attack and stroke, while screening potential drugs that can counteract this dysfunction.
Often described as the powerhouse of the cell, mitochondria produce the energy cells need to function. However, normal aging and age-related diseases like heart attack and stroke can disrupt mitochondrial function. Castle鈥檚 research investigates two specific triggers of mitochondrial stress: calcium and reactive oxygen species, which are highly reactive molecules that contain oxygen.
When calcium and reactive oxygen species levels surge, they can open a channel in the mitochondrial membrane known as the mitochondrial permeability transition pore. Once opened, the pore disrupts normal energy production. In response, the cell activates a pathway called the mitochondrial unfolded protein response.
鈥淣ormally, this response helps repair misfolded proteins in the mitochondria,鈥 Castle said, 鈥渂ut our lab discovered that when the pore remains open for too long, this response can become maladaptive. Instead of protecting the cell, it actually switches and it becomes detrimental to the cell. This whole cascade of the pore and then this unfolded protein response together can lead to further dysfunction in the cell, potentially leading to cell death.鈥
鈥媁hile the pore does not cause a heart attack or stroke, it plays an essential role in the cellular response to tissue damage after oxygen flow is restored. As people age, their cells become less efficient at clearing reactive oxygen species and regulating calcium levels, making them more susceptible to the pore opening.
To study these pathways during aging, Castle is conducting experiments using C. elegans, which have mitochondria nearly identical to those in humans. Because the nematodes have short lifespans, Castle can track age-related cellular changes over approximately one month.
In the lab, Castle manages large populations of genetically modified nematodes with glowing proteins. She uses fluorescence microscopy to observe proteins glowing at different wavelengths, revealing cellular activity. With the new NIH funding, Castle will take her research a step further, testing her findings in mammalian cell cultures to confirm their biomedical relevance to human health.
The research aims to help scientists better understand these cellular processes, apply their findings to human health and reduce the effects of age-related diseases and medical emergencies.
While the award is a testament to Castle鈥檚 research and determination, she emphasized that earning it was a group effort. She worked closely with faculty and staff to develop and refine a compelling proposal and grew as a researcher through Angeli鈥檚 pilot project funding from 91福利鈥檚 Center for Biomedical Research Excellence.听
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鈥嬧”I’m incredibly grateful to my mentor, my committee, my lab members and the University of Maine for creating this type of environment that allowed me to be successful and pursue this opportunity,” Castle added. “I’m definitely very excited to start this work and get some good results.”
Beyond funding essential lab reagents, cell lines and conference travel, the award recognizes Castle鈥檚 accomplishments and potential as a biomedical researcher.
鈥”The Molecular and Biomedical Sciences Department has been around at 91福利 for a really long time, decades,” Angeli said. “Alyssa is the first student in our department to receive this fellowship. It’s an exciting and important achievement, and we’re really glad that she was able to earn it.鈥
Story by Yoana Karageorgieva, research media intern
Contact: Daniel Timmermann, daniel.timmermann@maine.edu
