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Functional characterization of schizophrenia rare variants using genetically engineered human iPSCs

Award Number: R01MH129277
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Functional characterization of schizophrenia rare variants using genetically engineered human iPSCs - PROJECT SUMMARY Schizophrenia (Scz) is a common and debilitating neurodevelopmental disorder. However, the genetic architecture of Scz is highly complex, impeding research progress. Recently, the Scz Exome Meta-Analysis (SCHEMA) Consortium has identified genes with ultra-rare coding variants that each confer substantial risk for Scz. We hypothesize that the presence of these rare variants in human induced pluripotent stem cells (hiPSCs) will lead to neuronal phenotypes relevant to Scz. The PI, Dr. Pan Li, has extensive experience with gene editing and iPSCs, including development of an improved method for seamless introduction and removal of mutations into hiPSCs. She has previously focused on neurodegenerative disorders, but with this application proposes to change to study of Scz. This transition is facilitated by the location of her lab in the Division of Neurobiology, which has a long track record of research into major mental illnesses and of highly collaborative research using iPSCs (eg the HD iPSC Consortium). In Specific Aim 1, isogenic hiPSC lines with protein truncating variants associated with Scz will be genetically engineered by CRISPR-assisted homologous recombination to generate panels of iPSC lines, with each isogenic line bearing a different N-terminal protein truncating point mutation. Knockdown and overexpression rescue experiments will determine whether there is loss of protein expression and thus loss of gene function. In Specific Aim 2, the effect of mutations on gene and protein expression will be studied using RNA seq and quantitative proteomics. In Specific Aim 3, the effects of mutations on synaptic and electrophysiological phenotypes will be delineated. We hypothesize that understanding the cellular phenotypes and altered signaling pathways evoked by the SCHEMA mutations will clarify the cellular pathogenesis of subtypes of schizophrenia, and provide potential therapeutic targets.


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 = $691,805 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	4	12/23/2025	NON-COMPETING CONTINUATION	$691,805
														Subtotal = $691,805

Issue Date FY: 2025 ( Subtotal = $699,992 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	3	12/4/2024	NON-COMPETING CONTINUATION	$594,993
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	001	3	9/23/2025	NON-COMPETING CONTINUATION	$104,999
														Subtotal = $699,992

Issue Date FY: 2024 ( Subtotal = $703,284 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	2	11/13/2023	NON-COMPETING CONTINUATION	$632,956
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	001	2	8/15/2024	NON-COMPETING CONTINUATION	$70,328
														Subtotal = $703,284

Issue Date FY: 2023 ( Subtotal = $696,676 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Mental Health Research Grants	000	1	12/27/2022	NEW	$696,676
														Subtotal = $696,676

Grand Total All Awards = $2,791,757

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Functional characterization of schizophrenia rare variants using genetically engineered human iPSCs

Award Number: R01MH129277

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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