Melanie Cole, MS
(Host): Welcome to UF Vet Med Voice with the University of Florida College
of Veterinary Medicine. I'm Melanie Cole. And today, we're talking about
interstitial cystitis, bladder pain syndrome, new approaches for understanding
and treating bladder pain syndrome.

Melanie Cole, MS: And joining me is Dr. Aaron Mickle.
He's an Assistant Professor of Physiological Sciences at the University of
Florida College of Veterinary. Dr. Mickle, it's a pleasure to have you join us
today. I'd like you to start by telling us about patients with interstitial
cystitis or bladder pain syndrome and how they may suffer from chronic pain
that really severely affects their quality of life.

Dr Aaron Mickle: Yeah. Interstitial cystitis is a
disease that affects really broad range of people, primarily women, nine outta
10 are women. And it's thought to be within 5-10% of the population. It's a
very hard disease to diagnose and often it's diagnosed because a lot of other
diseases are eliminated. But it is basically a disease where you have
overactive bladder and a lot of chronic pain. And chronic bladder pain or
chronic visceral pain is very different than other types of chronic pain. And
so, we're really trying to figure out ways that we can better treat it.

Melanie Cole, MS: Well then, since pain is somewhat
subjective, can you explain how you feel that an understanding of the biology
of pain can help us to understand how to help people that suffer from various
pain syndromes?

Dr Aaron Mickle: For sure. Pain is very difficult to
study because it is a very subjective thing. Definitely in people, people have
different thresholds for pain, what they consider painful or what they consider
affecting their life. And so, what we're really doing is looking for different
molecular targets. So, opioids are often used for the treatment of chronic
pain. And this can lead to a lot of different downsides including opioid
dependence as well as addiction issues. So, what we're doing is looking at the
molecular signaling events within the bladder and seeing if we can identify new
targets that could maybe be used for a pharmaceutical therapy in the future to
help alleviate this pain.

Melanie Cole, MS: Dr. Mickle, as I understand it, in
your laboratory at the University of Florida College of Veterinary Medicine,
you incorporate multiple techniques at the system and cellular level to answer
questions related to mechanisms of bladder, sensory function and pain. Can you
tell us a little bit about some of the work that you're doing?

Dr Aaron Mickle: So, what has really interested me for a
long time, even before I started my PhD, was how different cells communicate
with neurons. So neurons, as we probably most appreciate, are cells that are
sending electrical signals around the body to tell the body where to move, how
it feels, whether you're touching a hot stove. But there's a lot of different
things that the neurons are doing besides that. They're communicating with
different types of cells. And so, what we're really trying to study is how the
endothelial cells or the urothelial cells in the bladder, so this is what lines
the bladder, forms the barrier that keeps urine in the bladder and out of the
body, how those communicate with the sensory neurons in the bladder.

And so, we're doing this with a number of different ways. One
of the main new ways we're doing it is using optogenetics. So, optogenetics is
a technique that's often used in neuroscience, which uses light-activated
proteins that we can then express in these urothelial cells. This means that we
can activate and manipulate these cells with light. And this is a really
profound technique that has revolutionized how we study neuroscience circuits.
But we think we can also use it to understand how we can study local bladder
circuit signaling. So, how these cells that normally are thought to be a
barrier to urine can provide sensory signals in disease states to influence
sensory neuron signaling. So, we do this a number of different ways with animal
models and looking at how manipulating these cells in vivo can change voiding function
as well as in cells in dish in the cell culture. So looking at when we culture
these cells with sensory neurons, they release different types of
communicating, signaling molecules that we can identify and then translate that
back into our animal models.

Melanie Cole, MS: That's fascinating. It's really
transforming the field of neuroscience, isn't it? So, I would like you to tell
us about your work with angiotensin signaling for developing and maintaining
disease symptoms. Tell us a little bit about that work.

Dr Aaron Mickle: So, this was the work that was just
recently funded by the NIH, and really looking at new targets. So, interstitial
cystitis is understudied in my opinion, and something that a lot of people are
looking for new therapeutic targets. And so, the angiotensin is something
that's studied throughout the body, primarily in hypertension. So, it's
probably something a lot of people are familiar with, blood pressure
modification medication like angiotensin receptor blockers or ACE inhibitors.
These all affect angiotensin signaling cascades. And so, what we're doing is
trying to look at the bladder and see what angiotensin is doing at the bladder
locally.

So, there's a lot of overlap in symptomatology. So, increased
reactive oxygen species, which can cause cell damage; increased inflammation
markers, as well as fibrosis that are seen in interstitial cystitis patients.
That is also seen in other organ systems with dysregulation of angiotensin
signaling. And so, what we're doing is really a basic science study where we're
trying to figure out what angiotensin signaling receptors are doing in the
bladder, because it's really unknown at this point. There's very few studies
that have shown that they're expressed there or even what they're doing. So, we
really are trying to figure out what they're doing and how they may influence
interstitial cystitis as a disease and how that may influence pain and
dysregulation of sensory function.

Melanie Cole, MS: Well, I hear, Dr. Mickle, you recently
received the prestigious Rita Allen Foundation Award for pain research to
further your aim to develop treatments for interstitial cystitis and bladder
pain syndromes. Tell us about that. That's pretty cool.

Dr Aaron Mickle: That was a really big honor. A lot of
big names in pain research have received that award and that is pretty much to
fund the Urothelial Sensory Communication Project. And so, that provides some
very flexible funding to explore different ways that we can better understand
how these endothelial cells are communicating to sensory neurons. And so, we're
taking a number of approaches, some of which I've already described using
animal models to manipulate the endothelial cells and how it influences sensory
function and pain. But we're also looking at seeing in the brainstem how these
endothelial signals are interpreted by the brain. So, we're using fMRI or brain
imaging to look at what brain areas are activated by activation of these
endothelial cells, and how that may change with disease models, really trying
to establish this method of optogenetic activation of the endothelial cells as
a way to better understand the sensory signaling in the bladder.

Melanie Cole, MS: Dr. Mickle, this is so interesting.
And I think the most important question to me anyway, is how do you envision
your research translating into care for human to veterinary medicine and vice
versa? Tell us how these results of your studies could open up new FDA approved
treatments with widely available and safe angiotensin inhibitors as you
mentioned, and that could substantially impact patient's quality of life. Tell
us how this could change the landscape of what you're researching.

Dr Aaron Mickle: That's really the end goal, right, is
to help patients and develop better treatments. And that's where I think the
angiotensin project really has some of the most direct translation. So, we have
a lot of drugs already that target these angiotensin signalings that are FDA
approved. And so, really, if we can develop ways to better understand the angiotensin
signaling system and if it's involved in interstitial cystitis, this is a
really direct route to use these already FDA approved drugs to help treat
patients with disease. Right now, we're also looking at patient databases. So,
looking at seeing how many patients with interstitial cystitis may have
hypertension or be on hypertensive-modulating drugs to see if there's overlap
and if people that are treated well for hypertension, they may have better
outcomes. And so, that could lead us to more indication along with our basic
science work that potentially using these angiotensin-targeting drugs may help
people with interstitial cystitis, reduce inflammation, fibrosis and the
symptoms of the disease.

Melanie Cole, MS: It's really great research that you're
doing, Dr. Mickle. And I hope you'll join us again and keep us updated as you
learn more. It's really an important topic. And for more information about the
UF College of Veterinary Medicine, please visit vetmed.ufl.edu/ufachievers. Or
to listen to more podcasts from our experts, you can visit vetmed.ufl.edu. And
that concludes today's episode of UF Vet Med Voice, brought to you by the
University of Florida College of Veterinary Medicine, advancing animal, human
and environmental health.