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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.
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