Sunday, December 14, 2025 12/14/2025

A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement

Award Number: R21OD033660
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

Group Awards By:

View Award Description

A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement - Project Summary: We aim to develop a new mouse model for studying diseases caused by GBA1 mutations in multiple organ systems. GBA1 encodes a lysosomal glucocerebrosidase (GCase) responsible for degradation of its glycosphingolipid substrates. Mutations in GBA1 gene disrupt GCase function and cause Gaucher disease (GD) that presents heterogeneous disease phenotypes in visceral or central nervous system (CNS) organs. Typical manifestations of visceral form GD1 include hepatosplenomegaly, anemia, thrombocytopenia and osteopenia. Neuronopathic GD (nGD, GD2 and GD3) are rapidly progressive CNS diseases leading to mortality and accompanied with visceral symptoms. GD affects multiple organs that align with the research mission of NIDDK (liver), NHLBI (lung), NINDS (CNS) and NIAMS (bone). GBA1 gene mutations are also genetic risks in developing Parkinson disease (PD). The approved therapies, Substrate Reduction Therapy (SRT) and Enzyme Replacement Therapy, are only effective in GD with visceral symptoms and do not treat CNS diseases. The effective disease modifying therapy is not available to treat PD. GBA1 mutation-caused diseases are complex affecting multiple organs. Faithful modeling of GD and GBA1-associated PD in an animal model is crucial to study the associated disease processes and to establish a clinically-relevant model for testing therapeutic approaches. A barrier in studying GBA1 mutation-associated diseases is the absence of animal models that recapitulate all aspect of human disease in multiple organs. Previously developed Gba1 mutant mouse models either show no detectable phenotype or affect restricted organs. Their nGD and PD phenotypes are very mild to absent. Our recent study has identified progranulin as a modifier of GCase. Deletion of progranulin in Gba1 mutant mice resulted in rapid progression of substrates accumulation, Gaucher-like macrophages and inflammation in liver, lung and brain organs, the typical GD phenotypes. This new model (termed PG9V) also developed neuronal phenotypes recapitulating nGD and PD. Our new PG9V model overcomes the limitations in the existing models. We hypothesize that genetic modification of Gba1 mutant mice by progranulin deletion impacts inflammation and glycosphingolipid metabolism in visceral and CNS organs, establishing a novel clinically-relevant animal model for GD and PD. We will characterize visceral GD phenotypes (Aim 1) and evaluate CNS phenotypes (Aim 2) in PG9V mouse model to establish criteria for testing therapies. Furthermore, we will test if SRT compound alleviate the disease in PG9V mice to determine preclinical value of PG9V model. This new GBA1 mutation-associated mouse model represents a major advance forward from existing mouse models. Comprehensive characterization of PG9V mice will facilitate pathophysiological studies and enables therapy evaluation and toxicity testing in a single model with multiple organs involvement.


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 = -$362 )
2026	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Research Infrastructure Programs	000	2	12/5/2025	NON-COMPETING CONTINUATION	-$362
														Subtotal = -$362

Issue Date FY: 2023 ( Subtotal = $203,124 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Research Infrastructure Programs	000	2	6/9/2023	NON-COMPETING CONTINUATION	$203,124
														Subtotal = $203,124

Issue Date FY: 2022 ( Subtotal = $258,500 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Research Infrastructure Programs	000	1	6/22/2022	NEW	$258,500
														Subtotal = $258,500

Grand Total All Awards = $461,262

Top

All Categories

About

Search

Reports

Data Submission

Award Information

A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement

Award Number: R21OD033660

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer