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

基本信息

批准号：
10508985
负责人：
Chuanju Liu
金额：
$ 25.85万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508985
关键词：
Acute Address Affect Age Age-Months Amyloid beta-Protein Anemia Animal Model Autophagocytosis Bone Diseases Brain Brain Pathology Central Nervous System Diseases Chronic Clinical Cognitive Complete Blood Count Complex Disease Disease Progression Enzymes Exhibits GRN gene Gaucher Disease Gaucher&apos s Cell Gene Mutation Genes Genetic Genetic Risk Glucosylceramides Glycosphingolipids Hematological Disease Hepatosplenomegaly Histology Human Inflammation Lead Liver Longevity Lung Lysosomes 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 Neuraxis 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 macrophage microCT mortality mouse model mutant mouse model novel novel therapeutics pre-clinical preclinical study success therapeutic development therapeutic evaluation

项目摘要

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.

项目概要：我们的目标是开发一种新的小鼠模型来研究 GBA1 突变引起的多器官疾病系统。 GBA1 编码溶酶体葡萄糖脑苷脂酶 (GCase)，负责降解其鞘糖脂底物。 GBA1 基因突变破坏 GCase 功能并导致戈谢病 (GD) 在内脏或中枢神经系统（CNS）器官中呈现异质疾病表型。典型的内脏型GD1的表现包括肝脾肿大、贫血、血小板减少和骨质减少。神经病性 GD（nGD、GD2 和 GD3）是一种快速进展的中枢神经系统疾病，可导致死亡和死亡。并伴有内脏症状。 GD 影响多个器官，这与 NIDDK 的研究使命相一致（肝脏）、NHLBI（肺）、NINDS（中枢神经系统）和 NIAMS（骨）。 GBA1基因突变也是遗传风险患有帕金森病 (PD)。批准的疗法：底物还原疗法（SRT）和酶疗法替代疗法仅对有内脏症状的GD有效，不能治疗中枢神经系统疾病。这尚无有效的疾病修饰疗法可用于治疗 PD。 GBA1突变引起的疾病很复杂影响多个器官。在动物模型中忠实地建立 GD 和 GBA1 相关 PD 模型对于研究相关的疾病过程并建立临床相关模型来测试治疗接近。研究 GBA1 突变相关疾病的一个障碍是缺乏能够在多个器官中概括人类疾病的各个方面。先前开发的GBa1突变小鼠模型要么没有表现出可检测的表型，要么影响受限的器官。他们的 nGD 和 PD 表型非常温和缺席的。我们最近的研究发现颗粒体蛋白前体是 GCase 的修饰剂。 Gba1 中颗粒体蛋白前体的缺失突变小鼠导致底物积累、戈谢样巨噬细胞和肝、肺和脑器官的炎症，典型的GD表型。这款新型号（称为 PG9V）还发展出概括 nGD 和 PD 的神经元表型。我们的新 PG9V 型号克服了以下限制：现有的模型。我们假设通过删除颗粒体蛋白前体对 Gba1 突变小鼠进行基因改造影响内脏和中枢神经系统器官的炎症和糖脂代谢，建立了一种新的 GD 和 PD 的临床相关动物模型。我们将表征内脏 GD 表型（目标 1）和评估 PG9V 小鼠模型中的 CNS 表型（目标 2），以建立测试疗法的标准。此外，我们将测试SRT化合物是否能缓解PG9V小鼠的疾病，以确定PG9V模型的临床前价值。这种新的 GBA1 突变相关小鼠模型代表了现有小鼠的重大进步模型。 PG9V 小鼠的全面表征将促进病理生理学研究并使得在涉及多个器官的单一模型中进行治疗评估和毒性测试。