|
Current Research Activities:
Cellular regulation and biochemistry of protein regulators of G protein signaling (R6S proteins).
Signaling and biochemical diversity among Gqalpha family members.
General Research Interests:
Cellular roles and regulation of a protein/RGS protein signaling pathways.
Please explain your research to the lay public.
G-proteins are critically important for basic function of hormones and neurotransmitters. If you envision a cell as a big water-balloon, and all cells as a conglomerate of water balloons, they have to communicate with each other: they're blind unless they can find a way to talk. So on the surface of cells, they have specific receptors that are able to detect messages sent from a neighboring cell in the form of either hormones or neurotransmitters. It's like a baseball mitt that will receive specific neurotransmitters.
Once that happens, binding of the neurotransmitter or hormone to the surface of the cell at a specific site causes that cell that had previously been asleep or 'quiescent,' makes it spring to life and do whatever that cell does. If it's a neuron, mediating neuronal function, or if it's a liver cell or heart cell, or even your eye, visual signaling, works the same way.
Binding of the hormone or neurotransmitter to its receptor causes that receptor to transmit a message from outside the cell to inside the cell. It does so by interacting with G-proteins. The hormone-bound receptor will reach out across the plasma membrane and tickle a g-protein which is nearby. The g-protein then initiates a signaling cascade.
If you envision it like a relay race, the hormone is the first messenger, and the challenge is to get the message from outside the cell across the outer membrane, and you have to get it to the inside, with the whole being like a water balloon and the inside being the watery part of the cell. G-proteins then sit on the inside surface of the cell or plasma membrane, which is called the cytoplasmic surface of the plasma or outer membrane of the cell.
So the receptor will reach out and tickle a G-protein, and that's like the first domino in a series of many dominoes which ultimately leads to the nucleus. So the g-proteins, their job in life is to link extra-cellular stimuli, either a neurotransmitter, hormone, visual signaling like a photon of light, taste, or smell- G-proteins are universally important for all aspects of cell and organ physiology. Their job is to serve as the middle-man, the linker, with the left hand they'll talk to the receptor, and detect when it's bound to a hormone, and with the right hand then, in turn, it will reach out and initiate a signaling cascade inside the cell that makes it spring to life and do its job, whatever the particular job may be.
What are your current research projects?
A few years ago, when they first discovered G-proteins, really about 15 years ago, in the beginning they thought there was just one or two. We now know that there are nearly 20 different g-proteins. And each of those carries out their own unique functions and are regulated in their own special way. Some are found in some tissues, others are found in all tissues. So trying to distinguish between certain family members and what their roles are in cell signaling and in particular cells is one of the challenges we're trying to face.
We focus on one set of families in particular- they're called the Gq family members. And they regulate cell calcium, and certain protein kinases. Cellular calcium is an important messenger. And probably one third to one half of all neurotransmitters and hormones act by mobilizing cellular calcium. And they rely on g-proteins in order to do that. So we focus on those particular family members that regulate cell calcium.
In addition, we now know that G-proteins initiate a signal, but it's not as simple as an on signal or an off-signal. We now know that the time, the duration, the amplitude of the signaling event that they regulate is tightly regulated and modulated. For example, it would be important that the on and off of a visual signaling event would be tightly regulated. If it weren't we'd be hallucinating all the time. And so there are a new family of molecules called the RGS proteins- Regulator of G-protein Signaling. They're newly discovered, and their job, partly, is to bind and regulate the properties of g-protein signaling. They modulate the time, the amplitude, and the duration of a signaling event. G-proteins can be viewed as a molecular switch. The hormone receptor will turn them on by binding guanine nucleotides. They turn them on and then RGS proteins, once they're on, regulate their actions.
In addition, RGS proteins have many other permanent unknown functions. There are nearly 30 different family members, and very little is known about these proteins, other than that they bind directly to G-proteins and regulate their functions. But the idea is that these proteins then modulate a broad range of, in most cases, unknown functions. So it's kind of the new frontier of G-protein signaling, trying to find out what roles these proteins play. Some of them have been implicated in a number of disease-processes. Certain G-proteins themselves are involved in disease processes. A number of sporadic cancers- pituitary tumors and a number of other cancers have been linked to G-proteins themselves. And the idea is that RGS proteins, mutations in them, will also be involved in a number of disease-states, although that's not yet been demonstrated.
They've been linked directly to certain types of colon cancer so far. One family member, known as axin, is critically important for animal development, and its been implicated in certain types of colon cancers. And another family member that we study has just recently been found to be involved with polycystic kidney disease. Another one that we study very carefully has been implicated in epilepsy and CNS [Central Nervous System] seizures.
In addition to these specific disease states, they have a universal role in regulating and modulating G-protein signaling. So these are some of the reasons we're interested these proteins. And actually, Catherine, who is in our lab, is working with one of these family members, RGS 14.
Why did you choose scientific research as a career?
I majored in Chemistry in college, but that wasn't enough to necessarily inspire me to pursue a career in science. What really sparked me to go into science is that I got a job in a lab just washing dishes. And when I began to compare how real science worked versus my experience in chem. labs, which are very dry, canned, and predictable, watching the scientists at work doing real science I thought was very exciting, and very challenging, and it was very different from chem. lab. Instead of following a set protocol, you were creating new protocols to try to attack scientific questions. I had a natural interest in science altogether, but the idea of doing it as a career really didn't hit me until that experience in the lab. I initially started out washing dishes just to help pay my tuition, but as I spent more time in the lab, my duties grew, and they began to involve me more and more in various aspects of actually running experiments and running them and carrying them out, and that's when I actually got hooked, because the process of discovery is so exciting to me. It also became clear that it was a long hard process as a career. Not all of the experiments worked, everything you tried didn't always go smoothly, and in that way it's different from chem. labs where it's designed to work every time if you follow the recipe.
But that's both good and bad. The frustrating part is that it can be long and slow, but once you hit on something new, and you make a discovery, it's really exciting each new day, you don't know what's going to jump out at you next, and that's what keeps it fresh and exciting and new. So in that regard, it's been thoroughly rewarding over the years, and that's what keeps you coming back- it's always a challenge, there's always something new and fresh and it's never-ending.
What interests do you have outside of your research?
I double-majored in chemistry and political science back when you could double-major. I had thought seriously about, strangely, third-world development and international business and law. With a slant towards international development or third-world development and developing nations. I'd made some serious inquiries down those roads about the same time I was working in the laboratory, so those two things were sort of competing with one another at the same time, and then I discovered science and really fell in love with it, at least real science, not just the subject of science but the process of conducting science.
How important is undergraduate research experience?
I think it's absolutely critical. When you talk about what we look for when we're looking for students, I think the experience of science counts just as much if not more than good grades. Graduate schools expect the students to be bright enough to handle the material, but they're not always looking for the ones that made all A's. Because there's a lot more to it than just good grades. And I think research experience counts most. Because, for example, I would not have discovered science had I not had that experience. There are a lot of people who don't know what to expect about the process. There are a lot of challenges, and there are a lot of long hard tough roads in the process of discovery. It's not unusual to spend months on projects that don't pan out. And sometimes that can be frustrating and discouraging. But for every one of those, there are those that do pan out. So you have to realize that that's sort of how the process works, that not everything you do always works, and that there can be unpredictable frustrations along the way.
You can only get that through research experience, and for that reason, graduate schools across the country really put an emphasis on research experience, in addition to good grades. Sometimes they'll take someone whose grades are solid but not perfect, with experience, over someone who has the higher scores.
How do you feel about teaching in the lab versus teaching in class?
I enjoy both. In the lab, one-on-one, it's a different kind of reward, and on some level it's a little more satisfying because you have more time to convey the nuances of a particular subject, and also you are teaching people all aspects of the subject; not only the technical approaches and how to think about approaching an experimental problem, rather than sort of the end-product, which is generally what you get in the classes. And you have more time one-on-one in lab, to really sit down and go over the details of a particular scientific problem, from a technical point of view but also, what's the experimental question, what's the broader implications of the findings that you might have, and then also you might get a result, but it's not always clear what it means. And the intellectual banter that you get in the laboratory, back and forth, and trying to figure out 'how you interpret this' and what does it mean and how does it impact the working models that you have.
Most of what we have in science, even though it gets to the textbooks after it's been rigorously shown by many different labs, we're always working with a model that is constantly morphing over time as we refine it. A good example are the RGS proteins that I mentioned earlier- they were completely unknown or unanticipated up until a few years ago, even though G-proteins were around for many years. They've completely challenged existing models of G-protein signaling. And those are the kinds of things that you get in the laboratory; it's fresh and new, basically the tired old phrase 'cutting-edge,' but it's true. You really are on the leading edge of the subject and you're five to seven years ahead of what you read in textbooks, typically. It takes about that long for new findings to find their way into the textbooks.
At the graduate level we tend to translate what we're doing in the laboratory to the classroom. There are topics that I cover, that we all cover in our lectures, that we may have discovered or read about last week. A brand-new observation that you wouldn't get, say, at an undergraduate level, typically. Often we don't even have textbooks at the graduate level. We'll rely on our own experience in lab, and the most recent findings from the literature.
|
