McLaughlin Institute

MRI Director Secures $2M Dollar Grant

McLaughlin Research Institute Director Dr. Mike Kavanaugh recently received a five year, $2.2M dollar grant from the National Institutes of Health to investigate how brain levels of the amino acid D-serine are regulated by a transporter known as SLC1A4, and how mutations in the human SLC1A4 gene cause neurological disease. This research involves studies of the linkage between SLC1A4 and N-methyl-D-aspartate receptors, receptors on nerve cells that play a critical role in triggering learning and memory. The receptor is normally activated when the neurotransmitter glutamate binds to it, but a less well-understood neurotransmitter, D-serine, is also required to activate the receptor. Kavanaugh and his collaborators discovered and cloned the SLC1A4 transporter gene over two decades ago, but its function in transporting and controlling D-serine levels was unknown until a couple of years ago. Disorders of the NMDA receptor/D-serine signaling system are associated with several neurological diseases including schizophrenia. Mutations in the SLC1A4 gene have also recently been linked to disorders of brain development in children. The National Institute of Mental Health awarded the MRI research team funding to establish how SLC1A4 works to modulate brain signaling in health and disease. The aims of the project include an effort by Dr. Deborah Cabin to test new drugs created by the group that target SLC1A4. The researchers will determine whether these drugs can alter brain D-serine levels and thereby modulate NMDA receptor function and synaptic plasticity. If successful, this could lead to a promising treatment for diseases like schizophrenia where low levels of D-serine contribute to disease onset and progression. In addition, collaborator Dr. Teresa Gunn will utilize the gene editing technology CRISPR/Cas9 to create transgenic mouse models that carry recently identified mutations in the human gene encoding SLC1A4 that are linked to neurodevelopmental and cognitive deficits, which would represent a promising breakthrough in providing new tools to understand and cure human disease.

 

An exciting new research collaboration with Eric Minikel and Sonia Vallabh at the Harvard/MIT Broad Institute involves testing a class of drugs called anti-sense oligonucleotides (ASOs) for efficacy against prion disease. Mouse models of prion disease are well characterized and recapitulate the effects of human prion diseases. We, along with Eric and Sonia, are testing ASOs developed by Ionis Pharmaceuticals in mouse models of prion disease, and have found that some ASOs significantly delay symptoms and extend lifespan. Pre-cllinical work at MRI is continuing using mouse models to support an application to the Federal Drug Administration for testing ASOs against prion disease in humans. While prion diseases are rare in humans, more common neurodegenerative diseases work by the same mechanism. A therapy that works against human prion disease could be tailored to work against Alzheimer’s, Parkinson’s and Huntington’s disease, and we hope to extend the work on prion disease to animal models for the more common diseases.

 

This past summer, MRI was delighted to host three student interns, Joseph Guter (Great Falls High School), Oliver Chinn (Sentinel High School, Missoula), and Isabel Gough (Whitman College). The interns worked on characterizing SLC1A4 function and the function of two SLC1A4 mutations known to cause disease in humans. Understanding how mutations affect the function of SLC1A4 will help us understand human disease. Normal SLC1A4 and mutant versions of the gene were expressed in frog oocytes, and the ability of the proteins to transport D-serine was assessed. The students found that one naturally occurring mutation increased D-serine transport, while a second mutation prevented the ability to transport at all. Introducing these mutations into the mouse will let us study the effects of varying D-serine levels in the brain, and provide a model for preclinical testing of drugs targeting SLC1A4.

 

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