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Disassembling the Mind
Jefferson Kinney took his first psychology class in high school. But he quickly found himself interested in far more than the theories of past psychologists. He wanted to learn more about the biology behind learning and memory. He wanted to know what changes in the brain result in neurological disorders. That curiosity shaped what he does today as a schizophrenia and Alzheimer's disease researcher at UNLV.
"I've been told I had a tendency to disassemble things when I was little," he said with a laugh. Which may be why he considers his research as the most interesting work he could ever pursue. "I get to chase down these curiosities and try to understand what is responsible."
With schizophrenia, Kinney's work involves examining, in animals, changes in a specific excitatory receptor (N-methyl-D-aspartate:NMDA) and an inhibitory receptor GABA (gamma-aminobutyric acid) that are involved in numerous processes including memory. Alterations in the function of these receptors have been implicated in schizophrenia and his research is directed at trying to understand how subtle changes in these signaling pathways may give rise to schizophrenia. He also hopes to find new targets for future drug therapies.
On the Alzheimer's front, Kinney and his group are working on understanding the role of several risk factors and subtle changes in cell function associated with the disease, including interactions between diabetes and inflammation in the brain in the onset and progression of Alzheimer's disease.
Briefly explain what you do.
We investigate changes in several aspects of behavior and try to determine the cellular and molecular mechanisms that may be responsible. These projects are specifically directed at understanding mechanisms in Alzheimer's disease and schizophrenia. We're trying to understand what's altered in these disorders that gives rise to the changes you see. There are a lot of really straightforward ways to do that in animal models, which is principally what we work with.
One of the greatest impediments to understanding, treating, and even diagnosing schizophrenia is that the neurobiology responsible for the symptoms is not known. In schizophrenia, brain function is altered -- most notably the connections between different brain regions may be disrupted. As a result you have hallucinations and delusions along with some pretty strong impairments in memory.
If you're able to prove this animal model of GABA or NMDA changes, then what?
First it's about understanding what's going on. If you chase down the mechanism, then you have a novel target for drug therapies. We've had good success for the NMDA part of it, and our GABA projects are now providing some new insights. We've landed on a number of different really effective ways to induce deficits -- to basically create aspects of schizophrenia -- in rodents. If the things that we think are altered in schizophrenia are established, then an entire new series of therapeutic targets opens up.
Animal models of Alzheimer's disease ...
A number of pathologies have been identified in Alzheimer's disease. However, the precise cause is not known. In my lab, we are examining the role of several risk factors, such as diabetes and chronic inflammation, on the onset and progression of the diseases in animal models. This work may provide valuable data on both the mechanisms responsible for the disease as well as provide potential therapeutic targets.
Finding the right animal model ...
Every novel therapeutic is first evaluated in animal models. If it shows promise, it is advanced to a clinical (human) setting. Numerous animal models exist that have been extremely useful in investigating the pathological features of Alzheimer's disease, but none completely match what is seen in patients since we do not yet know the cause. So, we have to ask, "Is the animal model being used to evaluate the drug the one we should be using?" and "Does this model have the most relevance to the clinical population we'll be testing the drug in?"
Answering those questions can help make sure that the treatments that advance to clinical trials have the best possible chance of success.
Collaborating with the Cleveland Clinic Lou Ruvo Center for Brain Health ...
We are part of a submitted grant that would establish a center for neurodegernerative research in Las Vegas and combine clinical research at the Ruvo Center with UNLV's pre-clinical research. The major component of my lab's work would be to contrast behavioral and biochemical measures taken in animal models with those from clinical patients to determine how well they correspond.
I've also recently begun collaborating with Ruvo Center researchers in the evaluation of a novel treatment for Alzheimer's disease. The center is currently performing a clinical trial on the drug Bexarotene, which was originally an anti-cancer drug that recently was found to produce dramatic improvements in an animal model of Alzheimer's disease. My lab is evaluating blood samples from clinical trial participants to determine if the drug is altering biochemical markers of the disease.
Alzheimer's urgency ...
The general public already knows a lot about Alzheimer's disease but we still need to pay more attention to it. Depending on whom you believe, between 8-20 percent of people age 65 have Alzheimer's and more than 50 percent of people 85 and older will be diagnosed with it. In 15 to 20 years, more than 40 percent of our population will be over 70. Some estimates are that the Alzheimer's spending, just for care, will be $1.1 trillion a year. That's crippling to a population. We need to find better ways of treating and diagnosing it.
Memory and the two disorders ...
Alzheimer's and schizophrenia do have a little overlap. Both disorders are characterized by impairments in learning and memory. While the deficits are different, if you understand at the cellular level some of the key players responsible for learning then you can start to examine what is altered in the disease(s). Finding these differences can be invaluable in understanding the disease and potentially how to intervene with treatment.
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