Sunday, December 14, 2025 12/14/2025

Pathophysiologic roles of protein-protein interactions at excitatory synapses and their modifications in schizophrenia

Award Number: R01MH138995
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2029

Group Awards By:

View Award Description

Pathophysiologic roles of protein-protein interactions at excitatory synapses and their modifications in schizophrenia - Abstract Genome-wide investigations of genetics, epigenetics and transcriptomics have identified hundreds of genetic variants playing etiologic roles in schizophrenia. Remarkably, pathway analyses of various algorithms consistently point to the synapse and biological processes therein as the most significant point of convergence. The next challenge is to find principles by which these genetic variants and dysregulation of those gene products conspire to precipitate synaptic pathology of the illness. NMDA receptor hypofunction underpins the synaptic pathology of SCZ; yet its pathophysiologic mechanisms remain unknown. We propose that defects in protein-protein interactions between key synaptic proteins drive NMDAR hypofunction in SCZ. Consistent with this model our preliminary data indicate that two distinct sets of protein-protein interactions are altered in SCZ. Previously, we found molecular evidence for NMDAR hypofunction, i.e., reduced tyrosine phosphorylation of GluN2A (encoded by GRIN2A) in schizophrenia. Subsequently this dysregulation was traced to hypoactivity of Src kinase, which in turn resulted from altered protein association of Src with a number of signaling partners. More recently, our preliminary studies showed that SCZ mutation of GRIN1 (encoding GluN1), G386C , reduces GluN1-EphB2 association altering NMDAR mobility and that GluN1- EphB2 association is reduced in patients. To test whether PPI might be an organizing principle for NMDA receptor hypofunction, we will focus three specific aims to examine how the two PPIs altered in SCZ impact nano-scale molecular events to cause NMDAR hypofunction and how we might rescue these defects. The aims are: Aim 1: Determine nano-domain specific spatial alterations in NMDAR complex proteins in SCZ. Aim 2. Delineate PPI alterations in NMDAR complexes in SCZ and their rescue by activating Src kinase. Aim 3: Determine the impact of SCZ mutations on the nano-organization of the spine synapse and their rescue by leveraging altered PPIs in SCZ. Together, these aims will test the hypothesis that the NMDAR protein-protein interaction network is a common pathway linked to SCZ pathophysiology. This will likely define new avenues of investigation and understanding of the cellular-molecularly mechanisms of SCZ and if successful, this work could identify NMDAR PPI modulation as an important new strategy for modulating SCZ pathophysiology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $671,768 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Mental Health Research Grants	000	2	12/10/2025	NON-COMPETING CONTINUATION	$671,768
														Subtotal = $671,768

Issue Date FY: 2025 ( Subtotal = $706,404 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Mental Health Research Grants	000	1	11/29/2024	NEW	$706,404
														Subtotal = $706,404

Grand Total All Awards = $1,378,172

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Pathophysiologic roles of protein-protein interactions at excitatory synapses and their modifications in schizophrenia

Award Number: R01MH138995

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer