# Glutamate receptors and human neurological disease > **NIH NIH R35** · EMORY UNIVERSITY · 2024 · $234,750 ## Abstract Abstract/Summary of my R35 Program This R35 Research Program proposal will use electrophysiological, molecular, and structural approaches to probe multiple aspects of excitatory synaptic function that are relevant for neurological disease. We will focus on the elucidation and modulation of the functional properties of postsynaptic glutamate receptors. We will take advantage of coincident advances in cryoEM, genetics, robotics, and receptor biology to address questions that were previously inaccessible. Four approaches will address critical gaps in our understanding of synaptic function and provide therapeutically-relevant insight into neurological disease. First, we will explore the functional and clinical implications of regional intolerance for variation in the healthy population as well as de novo disease-associated glutamate receptor mutations, most commonly found in GRIN1, GRIN2A, GRIN2B, GRIN2D genes that are among the least tolerant in the genome. We will establish the relationship in healthy individuals between allelic frequency and functional changes, which is necessary in order to understand the role of SNPs in these genes as disease risk factors. Evaluation of these rare variants will also provide opportunities for precision medicine, and advance our understanding of receptor function. Second, we will develop novel compounds for proof-of-concept studies to identify new therapeutic strategies for neurological disorders. We will synthesize subunit-selective modulators of agonist potency and channel open probability to assess the roles of understudied NMDA receptor subunits (e.g. GluN2C, GluN2D) in circuits in cortex, thalamus, and striatum. We will determine the site and mechanism of action of modulators of NMDA receptors, and use medicinal chemistry to improve brain penetration, potency, and solubility in collaboration with Dennis Liotta in Chemistry at Emory. We will use the pharmacological tools that we develop to gain insight into the treatment of epilepsy, stroke, Parkinson’s disease, and Alzheimer’s disease. Third, we explore biased modulators of NMDA receptors by developing the SAR of two classes of compounds that alter ion channel selectivity. These compounds represent the first example whereby a pharmacological agent can alter channel permeation properties, demonstrating that modulators can tune distinct functions of the NMDA receptor. These compounds hold enormous potential as neuroprotectants that diminish cation flux without side effects associated with receptor blockade, which we will evaluate in vivo in models of ischemia. Fourth, we will combine information obtained through genetic analysis of regional intolerance, mechanism of allosteric modulation, and new advances in structural biology to advance our understanding of the mechanisms that convert glutamate binding to channel opening. These experiments will focus on the shared regions of the protein that control channel opening, which are the key sites of action of ou... ## Key facts - **NIH application ID:** 10990153 - **Project number:** 3R35NS111619-06S1 - **Recipient organization:** EMORY UNIVERSITY - **Principal Investigator:** Stephen F Traynelis - **Activity code:** R35 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $234,750 - **Award type:** 3 - **Project period:** 2019-05-01 → 2027-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10990153 ## Citation > US National Institutes of Health, RePORTER application 10990153, Glutamate receptors and human neurological disease (3R35NS111619-06S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10990153. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*