Taking advantage of the body’s electrical system to treat disease

Let’s start with a couple of ice-breaker questions. What’s your favorite snack?  

Chips and salsa. 
 

What is your go-to karaoke song? 

I want to lean towards Radiohead songs, but I’ll just do a classic: “New York, New York” by Frank Sinatra. 

Do you have a bucket list? And if so, can you tell us about one or two items on it?  

I feel like I’m young and naive enough to still think I’ll live forever. I haven’t given it too much consideration. Maybe jump out of plane at some point in my life – skydiving.  

What brought you to University of Arizona and BIO5? 

I started at the University of Arizona in 2019 after my postdoc in Minnesota. I was drawn to the Department of Physiology for its well-rounded approach, focusing on multiple systems rather than one. It allowed each of us to have our own niche without overlapping, which complemented the ongoing research. It was a great opportunity for me. 

How did you decide on the research area you are focusing on? What motivated you to pursue it? 

Honestly, I stumbled into it. During my graduate studies, I focused on cardiovascular disease. However, within pregnancy research, I grew fond of the methodologies and models. Over time, I transitioned to broader areas like heart disease, cardiovascular, and renal diseases due to their significant impact. To this day, I still love that work.  

Can you share a recent revealing or exciting moment in your lab or research? 

So, we have been exploring the use of surgery to treat hypertension, or high blood pressure, which shows promise. We are now aiming to apply this technique to address other cardiovascular and kidney diseases.  

Recently, we’ve found success in treating polycystic kidney disease with this neurosurgical treatment. And what that means is simply cutting the nervous system connection between the kidney and the brain, slowing down the progression of the disease. This novel application offers hope for patients with limited treatment options.  

Currently, there is only one FDA-approved drug on the market for this condition from 2018. Unfortunately, despite the effectiveness of the drug in slowing down disease progression, patients' lives are significantly impacted by constant thirst and frequent urination, making bathroom visits the center of their existence. Moreover, long-term use is associated with liver toxicity, further complicating their condition. This disruption to daily life can also affect sleep quality. We aim to provide these patients and their physicians with alternative treatment options.  

Exploring combinational therapies targeting different mechanisms could potentially yield better outcomes, which is the focus of our latest research endeavors, and it is incredibly exciting. 

I have one question on this. If you are disrupting the pathway, are there any other negative effects to it? 

At present, there are not any well-documented negative side effects of the renal denervation procedure. Although complications like renal artery stenosis were initially a concern, they haven't been shown to occur more frequently than they would naturally.   

The only potential drawback is the loss of vasoconstriction ability, which could affect blood flow regulation in cases of hemorrhage or blood loss. However, this is not a significant issue unless treating patients engaged in activities like professional knife fighting. 

What are some of your research goals, and why is it important to study the peripheral nervous system? Could you elaborate on the significance of understanding this aspect and discuss some of your laboratory's research objectives? 

We are really fascinated by the peripheral nervous system as opposed to the central nervous system, i.e., the brain.  

The brain is like this black box that is difficult to manipulate, but the peripheral nervous system offers more control with fewer side effects. We can achieve this by selectively cutting specific nerve populations to observe how it impacts disease progression. Another exciting area is electroceuticals or neuromodulation, where we can modulate nerve activity without disrupting it entirely. This involves changing the nerve's signature to signal to the body that certain pathological signals are unnecessary or no longer present, potentially halting the disease cycle.  

I believe the future lies in this field, moving towards neuromodulation rather than simply nerve cutting. Understanding the signals we are manipulating will be crucial for advancing the field towards more effective treatments. 

You could also target other areas, not just focus on the kidneys or cardiovascular system? 

That's correct. It doesn’t have to be kidney or heart centric. 

Neuromodulation therapies are emerging nationwide, beyond renal nerves. For instance, vagal nerve stimulation, which modulates ascending and descending signals to mitigate or even reverse disease progression. You’re taking advantage of the body’s electrical system like hacking a computer. 

We need more of this! So, you're at the intersection of cardiovascular and renal diseases. Can you talk more about the connection between the two, or is it primarily through the peripheral nervous system?    

Yes, and to add to that point, many perceive high blood pressure as primarily a heart disease. While the heart plays a role, the kidney is central to blood volume regulation, impacting overall blood pressure. So targeting the kidney in models of hypertension is crucial for long-term blood pressure regulation. 

Your lab website mentions the use of telemetry-based approaches and acute electrophysiological preparations to assess changes in nerve activity and their effects on cardiovascular and renal responses. Could you explain these methods in simpler terms?  

In simpler terms, the telemetry-based approach involves implanting a device in animals to monitor their blood pressure and nerve activity over extended periods, like several months. This helps us track how diseases progress over time.  

On the other hand, the acute electrophysiological approach is more short-term and involves a surgical procedure under anesthesia. We use it to carefully manipulate the nervous system to observe its effects on nerve activity, blood pressure, and cardiovascular responses. 

I noticed your lab's website reflects a vibrant culture. Could you share how your team dynamics and culture influence the research environment and overall research experience? Additionally, I am curious to learn more about Bash. 

Sure, let’s start with Bash. He is a four-year-old Australian Shepherd and Catahoula Leopard mix, a breed I had not heard of until I got him during COVID. He has been my running partner and the lab mascot ever since! 

As for the team, I have been fortunate to have incredibly smart and awesome individuals in my lab, from the lab manager to postdocs, graduate students, and undergraduates.  

What is unique about our department at the University of Arizona is the large undergraduate program. I enjoy bringing undergraduates into the lab. They are eager for knowledge and experience. I believe in fostering a team-based environment where everyone works together towards common goals because success in the lab is shared. Also, I'm passionate about involving undergraduates in research to encourage them to pursue academic and PhD training and equip those interested in medicine with analytical skills that will make them better physicians. Graduating my first PhD student last Tuesday was both exciting and bittersweet. 

What lesson did your mentor impart to you? As a mentor yourself, especially to undergraduates, what principles or insights do you hope to instill in your students, considering they are at various stages of their academic journey? 

I have been fortunate to have several mentors throughout my career journey.   

One particularly influential figure was my postdoctoral advisor, John Osborn. He has been incredibly supportive of my career and development. One of the many lessons that I’ve taken from him is the team-based approach.  

It is crucial to constantly refocus on the hypothesis. How am I addressing the question? If I'm not, maybe I'm veering off into this little rabbit hole that I shouldn't be going down? Keeping it focused on the science and the underlying question is key to any research program and ensure that every experiment and analysis serve to address the central question at hand. We constantly talk about this in our lab meetings and daily discussions. This principle helps students maintain a perspective on broader scientific goals, even during the more mundane tasks like pipetting or sample collection.  

Another question we like to ask is what is your "why"? What motivates you and keeps you going in this line of work? 

If I had to do it alone, I'd be miserable. So, the "why" is science and the questions. But the "why" also includes the people. I love my lab and the people I work with.  

Do it for the people, do it for the science, do it for fun. It's fun to get up and answer some unknown questions. That's why we're academics in the first place. 

What’s next for you? 

What's next is that we're going to dive deeper into this polycystic kidney disease, or PKD. We just got a Research Project (R01) grant funded in December and it focuses directly on how the nervous system—peripheral nervous system, specifically the renal nerves—are contributing to the progression of this awful disease. 

We can try to mitigate either the early stages of it developing to change the disease's trajectory, or more clinically relevant, can we treat patients already presenting in the clinic with PKD. Can we offer them some sort of reversal? That would be the best-case scenario. But even if we can delay the progression or rapid progression of these cysts in the kidney, that will buy them time. 

How long does it typically take from having the idea to conduct human trials for a treatment like this? 

That is an area that we want to further develop within our research program. In my lab and here at the university, I want to see more of the basic science connection into more of a translational approach in the clinic. So, we are working on that right now.  

We have the chance to leverage this new technique that is freshly FDA approved and on the market for the treatment of hypertension. It is a catheter-based system. In essence, it is a tube that can access your kidneys' blood vessels, and from within that blood vessel, they can perform this nerve ablation. You do not feel it and the procedure is quick. It is like a light switch; you can turn it from on to off. You do not have to worry about taking a pill every morning.   

We want to translate that to other patients who may be hypertensive to move us towards clinical trials. We want to see if this is indeed efficacious for people that have limited options. 

Can you tell us what brought you onto your path to become a PhD? 

Early in my education, even as just a high schooler, I was mostly interested in writing. I love nonfiction, even to this day. I don't read much fiction; I don't have the capacity for it. So, when I went to college, I had the idea that I was going to go into journalism or become a writer. But I decided I did not like those classes. I found a lot of joy in my science classes instead and I changed my path into more science-based fields. I ended up with a triple major—it sounds like a lot, but there was a lot of overlap—biochemistry, cell and molecular biology, and chemistry. 

The reason I got into research was because of my organic chemistry professor, Viktor Zhdankin. Despite being one of the harder classes, I found it fascinating. When I talked to him during office hours, he showed me some of the reactions they were doing in the lab, and I was hooked. I joined his lab, published two papers in organic chemistry, and then took a hard left turn in physiology. It all started when I saw surgery being done on a rat and was immediately fascinated. I followed that interest to the University of Oregon for my PhD, focusing on hypertension in pregnancy. During my PhD, I realized my passion for non-traditional treatments like exercise. This solidified my decision to pursue academia, as I love answering questions, conducting research, and working with students. The energy of young minds keeps me motivated, and I have not looked back since. 

It's funny how life works out—I originally thought I would become a writer but ended up in science. However, it has come full circle because writing is a huge part of my daily routine now. Despite mostly writing dry, nonfiction science articles, it has been an inadvertent success. I owe a lot to someone who gave me an opportunity during my undergraduate years, and that is why I find it so important to pay it forward and bring others into the field. 

That's phenomenal. I wish there were more people in this world like that. Thank you so much for joining us. We really appreciate learning about your work and your lab. And for you taking the time with us today. 

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