NOS1AP

Transcription

(music playing) Dr. Bonnie Firestein: My name is Bonnie Firestein, I'm a professor at the Department of Cell Biology and Neuroscience. My laboratory is really focused on how neurons connect, how they communicate with each other, and what happens when this communication goes aberrant. One of our focuses is to look at neurodegenerative or neurocognitive disorders, so we're interested in a number of disorders including schizophrenia, and the project we're going to talk about today is a project looking at how a particular protein NOS1AP plays a role in the development of neurons and how it goes aberrant in schizophrenia. We take cells either from a control patients or patients with schizophrenia, and those are usually fiberglass or blood cells and we dedifferentiate them into induced pluripotent stem cells. We then take these and turn them into neural stem cells, and then eventually human neurons. What we know from Linda Brzustowicz's work, she is in the Department of Genetics, is that NOS1AP, the gene that encodes it, is linked to schizophrenia. We've done some cell biology and we know that if you overexpress NOS1AP or have too much of it, that dendrites, which are the input centers of neurons, don't form properly, you actually have less of them, so now we want to use a human system, where we know that in postmortem brain samples, this protein, there's too much of it in the area of the brain that's involved in schizophrenia, we want to know what it does to the human neurons, when there's too much of it and if we can reverse the effects, using antipsychotics or other drugs. So we're using cell biology so we culture the cells, we use biochemistry to try to understand what happens to the skeleton or the cytoskeleton of these neurons, we use chemical techniques, we stain for certain proteins, we use quantitative techniques to look to see how many dendrites we have, we use electrophysiology to look at how the neurons connect with each other, how they speak to each other and communicate, and have output. So right now we're at a critical point where we've taken control neurons and we've modeled them after patients with schizophrenia. So we've increased NOS1AP officially by inserting DNA, which will cause it to cause NOS1AP to be, for there to be more mRNA and more protein and what we've found is that there is a particular class of drugs that can reverse the effects, so for example this particular class of drugs will decrease the amount of NOS1AP that's in this cell, and will also reverse the decreased number of input centers or dendrites, so we think we can use this as a screening method for patients with schizophrenia to develop specific drugs or develop specific therapies for them. So, schizophrenia is a devastating disorder, there are many, many people who have schizophrenia, and it's a polygenic disease, meaning that there are multiple genes that lead to schizophrenia, it's not like, for example, sickle cell anemia, where there's one gene, and then you have sickle cell anemia. So we really have to devise specific therapies for individuals. Not all individuals with schizophrenia respond the same way to the same drugs, and so for us this is a really important step, kind of replicate schizophrenia in a dish, so that we can then go on, if we take cells for example from certain individuals, we can then devise specific therapies for them by kind of screening in the dish. So there are clinical applications so we can screen. We also might able to predict somebody who might respond better to certain drugs, we might be able to predict somebody who might develop schizophrenia at different time points in their lives, Linda Brzustowicz when she identified this particular gene, has a way of screening to see if people have this particular, it's called a single nucleotide polymorphism, or associated allele, that would lead to schizophrenia, so we do this basically as a group. A lot of our research is done in collaboration with Linda, as well as other members of the RUCDR, for example, Jay Tischfield, Jen Moore, we also collaborate with Ron Hart, so it's really a team effort, although my lab really focuses on the cellular aspects, and that's kind of our little niche in this whole project. So the next step would be now, and we have this going on, but we just don't have the results to share with you yet, is to actually take the cells from the patients with schizophrenia with the associated allele, and control patients, and then dedifferentiate and turn them into neurons and see if we see the same deficits in dendrites or input centers and then see if we can reverse it with the same drugs that we've used to reverse the overexpression phenotype. We can then branch out and start looking at other associated alleles, it doesn't just have to be NOS1AP for example, so we can look for people who have associated alleles in DISC1, which is disrupted schizophrenia, which has been linked to schizophrenia or many other different genes. We can even expand this to studies, for example, who have autism, children who have autism, so we're focusing on schizophrenia right now because the group is really interested in how we can help these people, but really a lot of our work is applicable to multiple neurocognitive disorders or neurodegenerative diseases, so we have a host of people working on it, we have postdocs and graduate students and undergraduate students, and one of the things I like to stress, because we' are in a university, and it's one of the reasons I came here in 2000, is that there are multiple undergraduate students who play a very large role in this project. So they have their own little parts in the project, they do independent research, they work with the graduate students, and the postdocs, and I think that's one of the really wonderful things that I kind of want to share with people is the fact that we have all levels, in fact we even have high school students coming this summer to start working on, maybe not this particular projects, but related projects, so I think it's important to know that this project is really a multiple effort. I couldn't do it myself and that the students and postdocs and everybody involved, collaborators were really important. (music playing)