Scientist‒Professor Pursues His Research While Also Supporting Student Researchers
Dr. Jeremy Rotty combines his passion for uncovering the intricacies of cellular sensing and response with a dedicated commitment to mentoring the next generation of scientists, fostering an environment of discovery and growth at the Uniformed Services University.
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Rotty Lab outing, 2022. Left to right: Summer Paulson, Sophia Liu, Rohini Manickam, Dr. Jeremy Rotty, and Matthew Stinson. (Photo courtesy of Dr. Jeremy Rotty) |
February 8, 2023 by Vivian Mason
Jeremy Rotty, Ph.D., assistant professor in the department of Biochemistry and Molecular Biology (BIO) at the Uniformed Services University (USU), feels very fortunate that he’s able to do what he loves—studying how cells sense and respond to their surroundings. “I’ve always been fascinated with how cells are able to respond to the world around them,” says Rotty. “It’s one of the things that’s really captured my interest through the years.”
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Dr. Jeremy Rotty, researcher, scientist, and professor in the department of Biochemistry and Molecular Biology at USU. (Photo credit: Tom Balfour, USU) |
In his studies, Rotty has found that cells have a complex and dynamic system of sensing and responding to changes in their environment that allows them to adapt and survive in a wide range of conditions. To do this, they can use a variety of mechanisms: cell surface receptors, intracellular signaling pathways, and altered cytoskeletal dynamics.
Cell surface receptors can detect changes in the extracellular environment and initiate intracellular signaling cascades. These cascades can activate or inhibit various intracellular signaling molecules that can regulate the activity of other intracellular molecules and affect the cell's behavior. Ultimately, Dr. Rotty is most interested in how these intracellular changes regulate the actin cytoskeleton to drive dynamic cellular processes like cell migration and phagocytosis of pathogens.
What it all boils down to is stimulus and response.
“For example, when an organism senses light,” notes Rotty, “it sees that light and then goes to it. So, there’s an external stimulus eliciting a response. In a similar way, cells react to an external stimulus that they can sense and respond to. That sensing is usually through receptor proteins that are in their cell membranes.” Thus, they can sense where those membranes are being activated and orient their response in that direction.
Research in the Rotty lab is focused on how cells orient themselves to that response. “We’re trying to understand if that ability to respond is broken,” Rotty explains. “What’s the consequence for these cells or for the organism as a whole?”
Basically, all cells sense their environment in some way, but some are especially responsive. Macrophages, white blood cells involved in sensing invading pathogens and responding to tissue damage, and microglia, specialized macrophages in the central nervous system, are highly sensitive and reactive. They have to not only detect potential pathogens, but also go wherever there’s been a breach in the body’s defenses.
Rotty and his researchers are also currently investigating immune cell behavior, in particular how macrophages respond to their environment by making membrane extensions that physically sense the world around them. This may mean a migrating macrophage interacting with its extracellular matrix or with a pathogen it needs to take up and digest.
“We know some of what drives that process,” says Rotty, “but one of our student researchers, Rohini Manickam (a fourth-year graduate student in the Molecular and Cell Biology program who won the Graduate Student Leadership Award), is working on understanding how the understudied protein Phactr4 regulates Arp2/3 complex function.”
Arp2/3 complex is critical for many types of membrane extensions involved in extracellular sensing, so an interaction between these two proteins could have significant implications on how immune cells like macrophages do their jobs. The Rotty lab hopes that greater understanding of how macrophages and microglia respond to their world will lead to a better understanding of how they become activated in the context of immune disorders.
“Rohini’s working on a research question that I’ve been interested in since my postdoc days, but never had the opportunity to pursue,” Rotty says. “Are there Arp2/3-regulating proteins that we don’t know about? The answer seems to be yes.”
He adds, “We think one of the most compelling examples is Phactr4. It’s known to play a role in cell membrane protrusions, and its new connection to Arp2/3 potentially provides mechanistic insight into why that is the case. Rohini has seen connections that I didn’t see. She’s also proposing her own hypotheses, and they seem to be panning out.”
There’s also a neuroscience angle to Rotty’s work, and he confides that student researcher Summer Paulson, a third-year student in the Neuroscience Graduate Program who won the Neuroscience Graduate Program Senior Student of the Year Award, is working with microglia. He boasts that she’s taking the lab in a new direction because her neuroscience expertise isn’t necessarily in the wheelhouse of the lab.
“Summer is coming at things from a very neurocentric perspective,” Rotty notes, “which is not at all my training background.” Thus, she’s able to incorporate new ideas and take the research in her own direction.
“Neuroinflammation is a huge, ongoing topic in the biomedical sciences,” divulges Rotty. “I would argue that we don’t understand it nearly as well as inflammation that occurs in other parts of the body. So, Summer’s focus is on investigating how the microglia sense and respond to their environment, specifically via a protein family called complement.”
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The Rotty Lab in May 2023 at the awards ceremony. Left to right: Sophia Liu, Rohini Manickam, Dr. Jeremy Rotty, Summer Paulson and Matthew Stinson. (Photo courtesy of Dr. Jeremy Rotty) |
Canonically, the complement cascade triggers a complex immune response that, in part, leads to “tagging” of potential pathogens with complement proteins that are sensed as “eat me” signals by phagocytic cells like macrophages and microglia. Microglia in the brain also have a homeostatic function that depends on complement. They make sure that the neurons are wired properly and that there’s not a lot of extraneous connections between neurons.
“Excessive synaptic connections could negatively impact neural function,” says Rotty. “For example, autism spectrum disorders feature just such a surplus of synapses. Conversely, an excessive pruning response is thought to contribute to pathological synapse loss in traumatic brain injury, Alzheimer’s disease, amyotrophic lateral sclerosis, and muscular dystrophy.”
Dysregulated complement function has been identified in many of these contexts in human patients and preclinical mouse disease models. Remarks Rotty, “Summer is trying to understand how microglia can physically sense these complement cues and why that sensing is important.”
Continuing, Rotty explains that their research is focused on how cells orient themselves to that response. “Not so much the sensing,” he says, “but the response. In other words, we’re trying to understand, if these complement proteins are still present but you break that ability to respond to them, what is the consequence for these cells and for the organism as a whole?”
One primary context wherein microglia and macrophages are becoming activated when sensing their environment is via trauma or wounds. “That’s one of the reasons why we’re getting more and more into the neuroscience side of things because we think that these processes play a role in traumatic brain injury and other neuroinflammatory conditions,” Rotty explains.
If we can understand how these cells sense trauma or wounds, we can make their activation less detrimental in the long term while we preserve their activation in the short term when clearance of pathogens and dead cells via complement is important for healing. Then, we can potentially guide the outcome to a better place by ameliorating harmful sequelae during later stages.
Rotty’s lab has encountered challenges doing their research. “The cells that we work with have their own special challenges,” he acknowledges. “With microglia, it’s very difficult to model microglia cellular behavior without having primary cells, since standard cell culture lines often don’t behave like authentic microglia in every experimental context. The process of harvesting and prepping microglia and then using them in experiments can be quite time-consuming. As for macrophages, it’s been a bit challenging to manipulate the cells genetically.”
Even with these research challenges, and the ongoing challenge for every academic researcher of managing time and resources, Rotty won the Cinde Helke Award this past June. The award is for “his dedication to the welfare of the graduate students of USU.”
Says Rotty, “I was very humbled and honored to be given this award. I try to give students and mentees the tools and the space to be productive and to become better scientists by the time they leave here. And part of that means listening to them, supporting them, giving them what they need, and letting them know that everything I do is in their best interests.”
He adds proudly, “With Rohini and Summer, they’ve done an excellent job of taking my interest, running with it, and developing their own interests and their own direction. It’s very easy to see them developing as scientists. I like feeling as though I’m paying into that new direction and contributing to not only the science that’s being done, but also the scientists who are being produced by our research.”
Teaching, research, and mentoring are all a part of Rotty’s DNA. He admits that, “The atmosphere at USU is very team focused—everyone’s on the same page, everyone has the same mission, and everyone’s investing in the people around them. I’m lucky to not only be a part of that, but also to be an enthusiastic contributor.”
