AWARDED GRANTS

January 2023: Dr. Riley Perszyk, Emory University

Grant in partnership with Uplifting Athletes, Young Investigator Draft

Functional assessment of human GluN2B variants using a robotic patch clamp rig

Dr. Perszyk is doing a collaborative post-doctoral position between Georgia Institute of Technology and Emory University working with Dr. Craig Forest, where he combined his undergraduate and graduate fields of study to work on developing a novel automated patch-clamp electrophysiology system. This system augments traditional electrophysiology rigs to allow for unattended operation, thereby reducing the burden on the experimenter and accelerating data collection. Dr. Perszyk received his BS with highest honors in Mechanical Engineering from Georgia Institute of Technology. He completed his PhD in Pharmacology from Emory University and began studying NMDA receptors. His goals are to determine the fundamental differences in receptor function caused by genetic variants in the GRIN2B gene, which are a component of NMDA receptors, and lead to numerous neurological disorder.

December 2022: Dr. Stephen Traynelis, PhD, Emory University

The Impact of NMDA Receptor Potentiation on Synaptic Plasticity in GRIN2B LOF Variants

Dr. Traynelis is a Professor of Pharmacology and Chemical Biology at the Emory University School of Medicine in Atlanta, GA, and the Director of the Center for Functional Evaluation of Rare Variants (CFERV). For this project, the lab will test whether administration of an allosteric potentiator of NMDA receptors can rectify deficient synaptic plasticity observed in mice harboring a LOF GRIN2B variant.

Read more here.

December 2021: Dr. Hongjie Yuan, MD, PhD, Emory University

Functional Evaluation and Therapeutic Strategies for an Animal Model Harboring a Disease-Associated Gain of Function Variant

The glutamate N-methyl-D aspartate receptor (NMDAR) gene family, including the GRIN2B gene-encoding GluN2B subunit, plays crucial roles in normal brain development, learning and memory. A surprising number of genetic variants in GRIN2B gene have been identified in a wide range of neurological and neurodevelopmental disorders, including autism, developmental delay, and epilepsy that affect a child’s behavior, memory or ability to learn and carry mental, emotional, and economic consequences for the individuals, their families, as well as society. We propose to use multiple techniques to show how a gain-of-function GRIN2B-p.Ser810Arg variant identified in a pediatric patient with severe intellectual disability and seizures influences synaptic activity/connectivity, seizure threshold, and behaviors in a knock-in mouse line harboring the variant. We will also assess whether a set of NMDA receptor inhibitors (e.g. radiprodil, memantine and/or ketamine) are able to mitigate the abnormalities. Evaluation of the effectiveness of these inhibitors in an animal model with a GRIN variant could suggest new strategies of personalized therapies.

November 2020: Dr. Hongjie Yuan, MD, PhD, Emory University

Dr. Hongjie Yuan is an Associate Professor of Pharmacology and Chemical Biology at the Emory University School of Medicine in Atlanta, GA, and Deputy Director of the Center for Functional Evaluation of Rare Variants (CFERV). Dr. Yuan’s research program utilizes a multidisciplinary approach to translate basic research involving human glutamate receptor genetic variations toward understanding the functional consequences of the variants in glutamate receptor genes associated with neurological and neuropsychiatric disorders, including intractable seizures, epileptic encephalopathy, autism, intellectual disability, movement disorders, and schizophrenia. His research is funded by GRIN2B Foundation, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH), and the National Institute of Mental Health (NIMH/NIH).

Rescue Pharmacology and Therapeutic Strategies to Treat Pediatric Neurological Disorders Associated with a Loss-of-Function GRIN2B Variant

NMDA receptors (NMDARs) are channels that allow ions to pass through the membrane of cells in response to neuronal release of the neurotransmitter glutamate. NMDAR activation can trigger changes in the strength of connections between neurons, which are widely considered to be a cellular correlate of learning and may play a role in neuronal development. NMDAR subunit GRIN2B/GluN2B expression is dominant in brain during embryonic and early post-natal stage, and has been proposed to play key role in brain development. Genetic variations in GRIN2B gene have been identified in children with various neurodevelopmental disorders, including intellectual disability, autism, and intractable seizures that affect a child’s behavior, memory or ability to learn and carry mental, emotional, and economic consequences for the individuals, their families, as well as society. We propose to use multiple techniques to show how the GluN2B-Glu413Gly variant reduces NMDA receptor function, synaptic activity, and cognitive ability in a knock-in mouse line harboring the GRIN2B-p.Glu413Gly variant, which was identified in a female patient with developmental delay. We will also assess whether a set of NMDA receptor potentiators and activators (e.g. D-serine, D-cycloserine) are able to rescue the deficits. Evaluation of the effectiveness of these potentiators in an animal model with a GRIN variant could suggest new strategies of personalized therapies. Some of the FDA-approved GluN2B-selective positive allosteric modulators we are testing have been shown to be safe in a pediatric population, and might warrant consideration as an add-on therapy in pediatric patients with GRIN2B variants. We will also make a knock-in mouse harboring gain-of-function GRIN2B-p.Ser810Arg variant, associated with severe intellectual disability and seizures.

November 2019 – October 2020: Dr. Tim Benke, The University of Colorado

Dr. Tim Benke

Dr. Benke completed his M.S. (Electrical Engineering, Rice University), Ph.D. (Neuroscience) and M.D. as part of the Medical Scientist Training Program at Baylor College of Medicine in Houston, TX. During his Ph.D and while a post-doctoral fellow training with Professor Graham Collingridge FRS at the MRC Centre for Synaptic Plasticity/University of Bristol, UK, Dr. Benke began to study the molecular mechanisms of synaptic plasticity, learning and memory. After completing his clinical training in Pediatrics and Pediatric Neurology at Texas Children’s Hospital, Dr. Benke was recruited to join the University of Colorado, School of Medicine and Children’s Hospital Colorado in 2002. Since then, his laboratory has studied the molecular mechanisms that are impacted by early-life seizures to cause intellectual disability and autism.

GRIN Variant Patient Registry

Dr. Tim Benke is the Principal Investigator for the GRIN Variant Patient Registry, which collects critical patient data from the entire family of GRIN variants: GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A and GRIN3B. There are no clinical trials currently for GRIN disorders. The data from the registry is needed in order to inform the broader community, especially industry and the FDA, in order to design and implement successful clinical trials in the years to come.

Learn more about this important registry and how to enroll here.

November 2019: Dr. Caitlin Hudac, University of Alabama

Dr. Caitlin M. Hudac is an Assistant Professor at the University of Alabama in the Center for Youth Development and Intervention (CYDI) and the Department of Psychology. Her program of research examines how the brain develops from birth through adulthood with a focus on potential areas of divergence associated with neurodevelopmental disorders (e.g., autism spectrum disorder, ASD; intellectual disability, ID). The goal of her work is to target critical functional aspects of brain development (e.g., language and social perception, attention, neural organization) to better measure specific phenotypes and serve as a biological indicator or “biomarker” for tracking intervention success.

Linking Brain and Behavior: A GRIN2B Biomarker

Currently, there is a lack of information linking quantifiable functional behavioral and neural profiles in humans to preclinical models of GRIN2B (e.g., mouse models of Grin2b haploinsufficiency). In order to best prepare for clinical trials and other treatment-focused empirical research, it will be important to establish human EEG biomarkers given the rapid progress of advances from molecular biology and cellular neuroscience. This study seeks to capture a promising electroencephalography (EEG) based candidate biomarker (i.e., biological indicator) that can aid in the development of effective clinical treatments and interventions. We will measure automatic auditory attention while children wear an EEG net and are at rest. This project directly addresses the GRIN2B Foundation research priority areas in several key ways: (1) EEG biomarkers will aid in the interpretation of GRIN2B function, by capturing real-time picture of the neural process by which children with GRIN2B mutations think; (2) This project will generate an in-depth understanding of how the clinical phenotype relates to brain function; (3) This candidate biomarker can potentially be used as a clinical outcome assessment. This project will teach us about how brain markers of attention relate to the clinical behaviors observed in children with disruptive GRIN2B mutations. Testing a brain-based biomarker will prepare us for clinical trials and other treatment-focused research. The translational nature of this study will provide valuable information regarding individual differences and phenotypes that will assist the development of precision treatment/s for children with GRIN2B.