HomeInVivo Biosystems Blog17 Minutes of ScienceSeventeen Minutes of Science: Understanding Mechanosensitive Channels Through C. elegans

Seventeen Minutes of Science: Understanding Mechanosensitive Channels Through C. elegans

Tune in weekly to our virtual series "Seventeen Minutes of Science" every Tuesday at 11am PST / 2pm ET where we go live on Facebook with a new guest each week to talk about how science and biotechnology is woven into their lives for (you guessed it) 17 minutes!

For episode 52 of 17 Minutes of Science we sat down with Dr. Valeria Vásquez from The University of Tennessee Health Science Center to talk about mechanosensitive channels - what are they, why are they important, and how is the Vasquez Lab utilizing C. elegans in their research.

The Vásquez lab aims to understand the functional, structural, and molecular mechanism by which mechanosensitive channels respond to mechanical stimuli and help delineate a general framework for their roles in health and disease. The lab follows two main avenues: 1) in vitro biochemical and biophysical approaches to study protein-protein and protein-lipid interactions of bona fide mechanosensitive channel complexes, and 2) in vivo approaches to characterize mechanosensitive channels in C. elegans having novel physiological roles.


Dr. Chris Hopkins (Host): [00:00:09] Hello there, my name is Chris Hopkins, we got you here on 17 Minutes of Science. This is the show that explores the world of science and how it affects both the starting academic and the seasoned professional. Today I have is a special guest, Valeria Vásquez. She joins us from the Health Sciences Center at the University of Tennessee. Hi, Valeria. How are you doing today?


Dr. Valeria Vásquez (Guest): [00:00:31] Good, Chris, how are you? Thank you for having me.


Dr. Chris Hopkins (Host): [00:00:34] Oh, thank you. Well, on 17 Minutes of Science, we probe into a lot of questions. And I would like to ask members of the audience if you feel free to please, chat us a question any time here. So as a quick intro for Valeria, she's an associate professor at the Health Sciences Center at the University of Tennessee. Her lab studies mechanosensitive channels, basically dysfunction in these sensory receptors are implicated in a broad range of diseases, you know, anywhere from heart arrhythmias to sciatica, chronic pain. You know, basically today's subject matter is going to be understanding the mechanosensitive channels through looking into C. elegans. And so with 17 minutes and we're already got a minute. Let's start in with some questions immediately for you. Valeria, can you tell us a little bit more about your research into mechanosensation and how you got started in all of this?


Dr. Valeria Vásquez (Guest): [00:01:28] Thank you again, so my lab studies how fatty acids, modulate ion channel function. We have - we are particularly interested in mechanosensitive ion channels, which are channels that sense force either through the membrane or the axis cytoskeleton. In my lab particularly, we study those that are modified by the membrane composition. I started these in my grad school, I did my thesis with Dr. Eduardo Perozo, at the University of Virginia. Back then I used to work with bacteria, so I used to work with a diet of C. elegans and we were studying the prokaryotic mechanosensitive ion channels from a very biophysical point of view. So we were studying a structure function and how the these membrane pores sensed the lateral tension of the membrane and they would open. So my interest started there. I learned electrophysiology, voltage-clamp, a little bit of microbiology. And when I was looking for my pot-doc, I, I knew I wanted to continue studying mechanical sensitive ion channels. And I happened to be in a meeting where Miriam Goodman was giving us sensational talk. And I really, really caught my eye because she was the only person working with, at the time, invivo electrophysiology, she was doing EM and I when I started digging into C. elegans, I think I just fell in love with how amazing the techniques were back then. And imagine now. So I asked Miriam to join her now because at the time also, we only knew about one eukaryotic mechanoreceptor complex that happened to be in C. elegans Receptor neurons and that Miriam and Martin Chalfie or Bianchi and many others were piling on a bunch of amazing data to demonstrate what were the sub units forming this mechano transduction channel complex. So at the time I wanted to combine what I knew with whatever was known in the field and try to understand, if at all, the membrane composition modified these mechanosensitive complex. So that's how we started working with C. elegans. And, yes, I don't know if you remember Chris, but when I saw when I was about to go on maternity leave, I was freaking out because I knew my project would be stalled for a few months. So Miriam heard about your company, I think Nema back in the day, right?


Dr. Chris Hopkins (Host): [00:04:03] Yeah. Yeah. It would've been Nema probably back then. Yeah, yeah.


Dr. Valeria Vásquez (Guest): [00:04:06] So we order a bunch of worms from your company because that was the way that we found - or Miriam found - to keep my project going well while I was on maternity leave. So that was really nice.


Dr. Chris Hopkins (Host): [00:04:18] Yes, we like to call it the call outsourced post-doc service that helps people out, keep carrying forth and keep, keep progress up.


Dr. Valeria Vásquez (Guest): [00:04:25] That made my maternity leave very relaxing because I knew the project was going. And then, so I finished my post-doc with Miriam and I moved to the University of Tennessee, where I'm currently at. Actually, my last week I received my tenured promotion.


Dr. Chris Hopkins (Host): [00:04:41] Oh, congratulations. That is awesome.


Dr. Valeria Vásquez (Guest): [00:04:45] Yeah. Since we started here, I have you used NemaMatrix and Invivo because you guys are post-docs away from the lab and that has helped a lot. A lot. So with C.elegans - so in the lab right now, I'm not working particularly to understand C. elegans, and I apologize to the worm lovers, but I'm more of a - I'm trying to use the beautiful profile of polyunsaturated fatty acid cascade of C. elegans to use those genetic backgrounds, or those genetic mutants, to understand how polyunsaturated fatty acids affect mechanosensitive ion channels. So that's the invivo part. Right now, we're also doing mice behavior, which is way more complex than I thought, obviously, but yeah, we keep working with C. elegans, very heavily.


Dr. Chris Hopkins (Host): [00:05:35] Well excellent, well that actually brought me to one of the questions I wanted to ask you which was sort of what other approaches are you integrating with C. elegans? And so the mice would be a really interesting subject there. So and a little bit just sort of what have you found about fatty acids? I mean, how impactful are they? How important are they for these mechanosensation channels?


Dr. Valeria Vásquez (Guest): [00:05:53] They are super important because they embed the membrane with particular mechanical properties so you can make a membrane really rigid if you have a bunch of saturated fatty acids or less rigid, if you have polyunsaturated fatty acids. So we have done those measurements in Miriam and my lab with atomic force microscopy, and it's really amazing how that can impact mechanosensitive ion channel function. We also have determined that a certain three channels are very sensitive to the membrane mechanics. Not to say that they are mechanosensitive, but they are very vulnerable or sensitive to the membrane composition. And I would expect that every membrane protein would have certain degrees of, of a sense in this membrane composition. So we use - we use, again, C.elegans  because the genetic background is really clean, so you can have either omega-3 PUFAs [polyunsaturated fats] or omega-6 PUFAs, or eliminate all of them. And then it's a really clean background that you don't have with mammals. Right. So in mammals, we can modify the diet and check on that. But with C. elegans, genetically, we just remove the Piezo1 and they're gone. And that's thanks to the work of Jennifer Watts and [00:07:12] Jim Bruce from [00:07:12] the C.elegans, back, you know, maybe 10, 15 years ago.


Dr. Chris Hopkins (Host): [00:07:19] And in fact, Jennifer Watts, one of her postdocs, is one of the founders of the company, Trisha Brock. So there's a pretty interesting connect there.


Dr. Valeria Vásquez (Guest): [00:07:29] Oh really? I'm such a groupie for Jennifer Watts' work.


Dr. Chris Hopkins (Host): [00:07:35] Well, let's jump onto the pezo-1. You've recently published in pezo-1 about mechanosensitive channels and food sensation. So now we got fluid, membranes, sensing food? Or, how does that all work?


Dr. Valeria Vásquez (Guest): [00:07:52] Ok, so, the pezo-1 story. So the family, the mammalian family is called PIEZO1, and the gene in C. elegans is pezo-1. When I started my lab, I thought that it would be very easy to characterize the knockout of pezo-1. And I thought that I would have like a dramatic, dramatic phenotype. And you guys made a knockout for us. You guys made a gain of function for us. And it turns out that all of the phenotypes were really, really mild. So really, really mild, to say the least. So what happens -


Dr. Chris Hopkins (Host): [00:08:26] That is always a sort of an intriguing, but common result. I think. They don't always live up to your expectations. So how did you adapt?


Dr. Valeria Vásquez (Guest): [00:08:35] Especially because the mammalian knockouts, humans and all, they have very either their embryonic lethal or they have really important phenotypes that cause diseases. So why worms have these gigantic gene and does not seem to be relevant. So one thing we found is might not be relevant for laboratory conditions, OK, because everything - you know, you are providing them food, you have 20 degrees. We have tried 15, 25, but it was never something is striking. So because we detected the expression on many others, a few at least three more laps at the same time to take that expression in the firings. It occurred to me that if we fed a different type of bacteria, we might have another phenotype. And I remember from my days in biophysics that to patch clamp E. coli, or  Escherichia coli, I used to use a protocol with an antibiotic, called cephalexin, that that makes filaments of E. coli. and then you add a lysozyme and they become a gigantic, well, its not gigantic but its big - to patch. So I told my post-doc at the time, Jonathan Millet, ay ay that maybe we should try using the cephalexin treated bacteria because it would be like feeding it spaghetti. Right. It would be like longer way longer than the control bacteria. And it turns out that really that phenotype that we had - we were really happy because it was the only the only time that we could see, oh, finally the knockout is different than the wild type and the gain of function mutant, or what we call the gain of function mutant is different than both of it. So that was really exciting because it's amazing how, you know, you have all this knowledge from previous projects and then suddenly like they merged together. So it was really nice. And that's when we came about talking about food sensation. And now the idea would be to use this knowledge to see how dependent is pezo-1 from PUFAs and fatty acids, which was the idea from the beginning, what we were never able to explore because the phenotype was so a mild.


Dr. Chris Hopkins (Host): [00:10:49] Well, excellent. And now we have basically, only about a six more minutes left here, so maybe we can take a little bit of a pivot on this. Interesting that basically, you know, eating spaghetti versus eating mush, it gives a very different - is literally leading to this mechansensation phenotype. So love that. You know, you've - uh, pivoting to perhaps a little bit different area, know the the social aspects in science. You have a unique aspect. You're married to another researcher. And in fact, you two work together side by side. So can you tell us a little bit about the some of the challenges of working side by side with your spouse and getting publications together.


Dr. Valeria Vásquez (Guest): [00:11:36] Well, yes, it is a challenge and some people are surprised and they always wonder how how can you resist working with your partner? Right. But it turns out that we met back in college in Venezuela, and so we came to the US with a purpose of getting a PhD. We - not even in my wildest dream, I thought I would have a my lab in the U.S., like I was always thinking of going back to my home country and then, you know, things got complex in my country and we weren't - you know, we like the style of living here and doing science. And so I have worked with mechosensitive ion channels almost since the beginning, I joined my PhD adviser lab, and he [my husband] was working with potassium channels. So we are always like working in similar things, but we're always trying to learn different techniques. So we address questions using both of our brains. Right. So then for our post-doc, when I moved to Miriam at Stanford, he moved with David Julius at UCSF. So he learned a bunch of things about sensory neurons, and nocirecepton and heat sensation in mammals. And I learned a ton with Merriam's and C. elegans. So when we joined the lab, we started to - all the questions we couldn't answer before because it was like, it was not part of the of our labs before we tried to, you know, combine all of what we knew to answer questions. So, for example, we had a paper that came out in January this year, I believe, where we answer what TRPV1 express in C. elegans thanks to the work of Cornelia Bargmann. We made out, I would say a better worm with you guys, hers was back in the day like, I don't know, maybe 50 years ago. So we tried to answer all of the questions we had by combining our expertise and we determined that Phosphoinositide turns out to inhibit TRPV1, at least in our experimental conditions. So it's really nice because we have similar and different questions. And we have we have learned so many things away from each other that we can complement our science. So the lab, we run two labs, but again, we share materials, we instruments. And it's like a big group, let's say.


Dr. Chris Hopkins (Host): [00:13:51] All right, that's awesome to hear, it is, fantastic. I think that is, as we all know, is a big driver NIH loves to hear about collaborative activity between people, and who you bring to the table. And it's fantastic to have a lifelong partner that is also a strong collaborator, bringing unique and different background to -


Dr. Valeria Vásquez (Guest): [00:14:10] And on a personal level, if I may, we have a son. Right. So it's really, I wouldn't say really easy, but it's easier, I would say, in comparison to other families, because we can work from home or in the lab and we can take our at our son. It's like, continuum, some people don't like it because the line between work and home is not drawn very well. But we - I mean, like, I love what we do and I think he loves what he does do. So I see it - like I mean, I love it. I really like working with him with the things I'm doing right now. So it's fine.


Dr. Chris Hopkins (Host): [00:14:46] Well, you know, I think everybody can appreciate the blurred lines these days with COVID. You know, we're all - here I am in my own house running this, these interviews. And so we there is a lot of blur these days. So I think we all understand that that work life balance, you know, it's, it's - it can be a challenge, but it also can be enabling. I'm not spending a lot of time traveling from here and there. I'm actually getting a lot more done. I'm sure most other people, especially if you're doing a lot of writing and so on, you're getting on all of that stuff that you wanted to get published - get it done. So the, we basically have another two more minutes for for this - went pretty fast for us here. And we've talked about the basically some at least the piezo is one specific example in the mechanosensitive channel. What're some of your future directions you want to be going into, where do you see sort of your future implications, real world implications for your research and where you want to go?


Dr. Valeria Vásquez (Guest): [00:15:49] So one of the things I would like is to go is a study and tackle the mechanism by which fatty acids and the membrane modulate these channels. Most of the publications we have although are really quantitative. They are not providing any mechanism because this channel is very, very weak. It has 38 membrane segments. So tackling the sensor of the membrane tension or things like that would take a huge amount of effort from the community. So I would like to have a molecular mechanism. In the meantime, we're doing some experiments towards that, but we are also making some lotions to use these fatty acids to inhibit as much as possible pain. So for that, we're using mice behavior and that's one of the things that my lab is really concentrating their efforts on. And hopefully next year I would have some like a roundup story to publish about that, because I think this is the first time I have something that has some translational capabilities. So - which was surprising because I was not looking for it, but I think it would be it is very exciting move away also from the mechanism towards more translation. But needless to say, we will try to understand how the membrane modulates this pezo or family of ion channels. I cannot hear you, Chris.


Dr. Chris Hopkins (Host): [00:17:17] Sorry - you can hear me now. Very interesting. So you know, the translational aspect to your to the research you're doing, you might be moving in and becoming an entrepreneur. Coming up with the lotions and a question from one of our members in the audience. Are those lotions for human use? And I presume so, right?


Dr. Valeria Vásquez (Guest): [00:17:37] That's a dream. Yeah, I have. I have partnered with a collaborator at the NIH and we we're working on it. I cannot give too many details because we don't have too many details. It's not that I want to keep a secret, but I don't want to jinx it. But that's the goal. That's the goal. And I assume they would be safe given the composition, because it's just fatty acids. And I think my - our last paper on that was really obvious towards that - I mean, like, essentially the last paragraph of the discussion was, you know, the goal is to use these to what it's going to ameliorate mechanical or mechanical pain. Right.


Dr. Chris Hopkins (Host): [00:18:19] So I love it. And, you know, we burned up our time here. And I love hearing how your story is leading towards a translational impact. Almost sounds like almost a natural nutraceutical is lotions being developed, but very interesting area of it, love it. Alright, well thank you.


Dr. Valeria Vásquez (Guest): [00:18:38] It went very fast. Thank you, Chris. It was very smooth and fast.


Dr. Chris Hopkins (Host): [00:18:44] Yes. You're welcome. Well, thanks, everybody for attending. And thank you Valeria for speaking to us about your wonderful research. And I'm excited to hear more about how this all develops down the road. And thanks, everyone, for attending.


Dr. Valeria Vásquez (Guest): [00:18:57] Thank you so much.

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