Last fall, Charles Thodeti, Ph.D., got the kind of news every researcher hopes to receive: The National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health had made the first installment of a four-year grant worth $1.76 million. His topic? The mechanical control of coronary angiogenesis.
But in late winter, the arrival of COVID-19 changed things for researchers like Dr. Thodeti, an associate professor in the Department of Integrative Medical Sciences. Along with his colleagues – 120 faculty members and postdoctoral fellows – at Northeast Ohio Medical University, Dr. Thodeti and his lab team had to find ways to persist through the pandemic.
For safety reasons, wet labs (using drugs, chemicals and biological matter, as opposed to dry labs, where computer or other analysis is used) had to close, with limited exceptions to conduct essential research and careful oversight of animal models.
As Ohio begins to open up, NEOMED is cautiously and gradually reopening its research spaces. It is not easy.
“Research is an orchestration of activities, and recreating that takes time,” says Steven Schmidt, Ph.D., vice president for research at NEOMED. “The University has provided specific guidance to researchers regarding the necessity for social distancing and wearing masks or face coverings in the labs and other common spaces, as well as the need to schedule the use of shared spaces.”
How to move forward? A conversation with Dr. Thodeti reveals that the life of a faculty researcher consists of many responsibilities beyond time in the lab.
How have you been spending your time recently?
My lab team and I have been working remotely, using the time to finish writing manuscripts (research findings from our lab, a comprehensive review of the literature in the field, methods pertaining to our research) to publish in scientific journals; to read research publications to keep up with the latest research In the field; and to plan new experiments. Further, we have written and submitted a supplemental grant to the NIH on cardiovascular complications induced by COVID-19 that aligns with our ongoing research.
I directed a Biomedical Sciences (Kent State University BMS) graduate course, “Cellular and Molecular Signaling,” that ended on May 5, 2020. I was also involved in planning a new curriculum module for the first-year College of Medicine curriculum, called Cardiovascular Pulmonary Respiratory (CPR).
During this time, I have continued to participate in various service activities at NEOMED and nationally, including a physiology faculty search, thesis defenses, BMS programming, mentorship committees, reviewing grants for the NIH, editing and reviewing manuscripts for various journals, and serving duties as a member of the steering committee and chair of the fellowship committee for the American Physiological Society.
Let’s talk about your project researching the mechanical control of coronary angiogenesis. Can you explain the premise and goal?
When someone has a heart attack, one or more of the vessels that supplies blood to the heart is completely clogged. Because of the obstruction, the part of the heart tissue that does not receive blood dies within minutes. The individual must be taken to a catheterization lab at the hospital within one hour, or they could die. Though there have been many recent advances in the immediate treatment of heart attacks, the long-term management of these patients is a daunting task. This is because the remaining heart tissue cannot cope with the workload, and these patients develop heart failure over time.
One would expect the heart to grow more blood vessels to assist with the workload of the heart after a heart attack. But instead, the number of blood vessels in the heart declines progressively. Therefore, there is a tremendous interest in both academia and pharma to identify ways to increase blood supply to save the failing heart.
To do this, many researchers have focused on chemical factors that work on endothelial cells, which line each blood vessel and make new blood vessels. Other researchers have tried using stem cells to improve the blood vessel growth in the heart. Unfortunately, the first approach was not very successful, and the stem cell approach has shown limited success.
In my grant project, we take a different approach, focusing on mechanical forces in the heart.
The heart is a mechanical pump. Once it starts beating, it will not stop until you die. That means that the mechanical stretching of the heart imposes a lot of mechanical force on the cells in the heart.
There are three major kinds of cells in the heart: the heart muscle cells that pump blood (cardiomyocytes); cells that line and form blood vessels (endothelial cells); and the supporting cells (fibroblasts). In my first R01 grant from NHLBI, we worked on the role of mechanical forces on fibroblasts after a heart attack, which replaces the dead heart tissue with scar that restricts the injury.
We found that a protein on the membrane of the cells works as mechanosensory (which senses mechanical stretch force) and is required for cardiac fibroblast activation, which if uncontrolled causes cardiac fibrosis and heart failure. We found that by genetically deleting or inhibiting this protein with a drug, we were able to protect the heart from heart attack-induced damage in a mouse model.
In the current grant, we focused on the same mechanosensory protein and its effect on endothelial cells in the heart. In fact, this idea stemmed from our work on cancer. We found that this mechanosensor’s levels were very low in endothelial cells of the tumor, which showed numerous blood vessels and enhanced tumor growth. When we increased the expression or activation of this protein in the tumor endothelial cells, we found that the number of blood vessels decreased, and that tumor growth was reduced. This led us to the hypothesis that the mechanosensory protein may somehow act like a brake for blood vessel growth, especially when the heart is under high stress – for example, after a heart attack or working under continuously high blood pressure, which causes enlargement of the heart (hypertrophy) and eventually leads to heart failure.
If our hypothesis is true, deleting this protein exclusively in endothelial cells should increase blood vessel growth and protect the heart from heart failure.
To test this hypothesis, we generated mouse models where we can remove this protein at will, i.e., before the experimental induction of a heart attack, immediately after the heart attack, or a few days after the heart attack. This allows us to investigate if we can grow blood vessels at any time point and protect the heart from failing. Indeed, our latest results show that deletion of this protein increased blood vessel growth and protected the heart from hypertrophy-induced stress.
We are continuing this work with mouse models of heart attack, and we hope to understand the molecular mechanism that could help us in developing novel therapeutics for heart failure.
Have you been able to go into the lab at all? Did you have any mice models that needed to be taken care of?
Until recently, we could go to the lab on a limited basis to work on ongoing experiments but without starting a new experiment. We continue to breed the critical mice we generated for the ongoing project. However, we had to terminate some important, timely experiments.
When researchers are given awards, they have deadlines to meet. Were you able to work with the NIH to adjust the deadline?
Yes. All the funding agencies require annual reports with a deadline. These are unprecedented times and almost all of the research labs in the world have been impacted by COVID-19. Therefore, funding agencies – including the NIH – are accepting the request for delays in the progress reports.
What will be your next step when you return?
With reopening, we have already started going to lab and performing experiments in a limited way and are slowly ramping up.
Four people — two post-doctoral fellows and two Ph.D. students – normally work in my lab with me. My lab is part of a big open lab designated for the Heart and Blood Vessel Disease research group in the Department of Integrative Medical Sciences, which is located on the third floor of NEOMED’s Research and Graduate Education building. The entire open lab consists of bays with benches for doing wet lab research. My lab has two bays that can accommodate four to eight people.
In addition, we share individual side rooms for cell culture, animal surgeries and microscopy. Although we have enough space to maintain social distance to accommodate two to four people per lab at a time, the faculty in RGE 3rd floor, under the direction of our department chair William Chilian, Ph.D., proactively decided to work on scheduled times until we return to normalcy, limiting the number of personnel to one person per bay or per room at any given time, to avoid any possible exposure to COVID-19 between personnel.
Our schedules are managed centrally by the IMS Department business manager, Ileen Ciccozzi. This arrangement is working effectively without any conflicts. Moreover, everyone working in the RGE third floor, including my lab personnel, are strictly following the NEOMED guidelines, wearing face masks and gloves and washing hands frequently. We are slowly ramping up our research activities and hope to get back to normal!