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

研究GBA1突变相关多器官疾病的新小鼠模型

• 批准号: 10651885
• 负责人: Chuanju Liu
• 金额: $ 20.31万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651885
• 关键词: Acute; Address; Affect; Age; Age Months; Amyloid beta-Protein; Anemia; Animal Model; Autophagocytosis; Bone Diseases; Brain; Brain Pathology; Central Nervous System; Central Nervous System Diseases; Chronic; Classification; Clinical; Cognitive; Complete Blood Count; Complex; Disease; Disease Progression; Enzymes; Exhibits; GRN gene; Gaucher Disease; Gaucher' s Cell; Gene Mutation; Genes; Genetic; Genetic Risk; Glucosylceramides; Glycosphingolipids; Hematological Disease; Hepatosplenomegaly; Histology; Human; Inflammation; Lead; Liver; Longevity; Lung; Lysosomes; Macrophage; Measures; Metabolism; Mission; Modality; Modeling; Modification; Monitor; Mus; Mutant Strains Mice; Mutation; National Heart, Lung, and Blood Institute; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; Neonatal; Nerve Degeneration; Neurologic; Neuronopathic Gaucher Disease; Neurons; Neuropathy; Onset of illness; Organ; Osteopenia; PGRN gene; Parkinson Disease; Parkinsonian Disorders; Pathogenicity; Pathologic; Pathology; Phenotype; Platelet Count measurement; Pre-Clinical Model; Preclinical Testing; Process; Research; Risk; Safety; Spinal Cord; Spleen; Study models; Symptoms; Testing; Therapy Evaluation; Thrombocytopenia; Tissues; Toxicity Tests; Viscera; Visceral; Weight; abeta accumulation; aged; alpha synuclein; analog; beta-Glucosidase Stimulating Protein; body system; bone; clinically relevant; disease phenotype; disease-causing mutation; early onset; enzyme replacement therapy; evaluation/testing; gait examination; glucosylceramidase; glucosylsphingosine; human disease; improved; liquid chromatography mass spectrometry; microCT; mortality; mouse model; mutant mouse model; novel; novel therapeutics; pre-clinical; preclinical study; success; therapeutic development; therapeutic evaluation

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.

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