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.

项目摘要：我们旨在开发一种新的小鼠模型，用于研究由多器官中的GBA1突变引起的疾病系统。 GBA1编码负责降解其溶酶体糖体葡萄糖辣椒酶（GCASE）糖磷脂底物。 GBA1基因破坏GCASE功能的突变并引起Gaucher病（GD）这表明内脏或中枢神经系统（CNS）器官中的异质性疾病表型。典型的内脏形式GD1的表现包括肝肾上腺肿，贫血，血小板减少症和骨质减少症。神经疾病GD（NGD，GD2和GD3）是迅速进行性中枢神经系统疾病，导致死亡率和伴随着内脏症状。 GD影响与NIDDK研究任务保持一致的多个器官（肝），NHLBI（肺），Ninds（CNS）和Niams（骨骼）。 GBA1基因突变也是遗传风险发展帕金森病（PD）。批准的疗法，底物还原疗法（SRT）和酶替代疗法仅在内脏症状的GD中有效，并且不治疗中枢神经系统疾病。这有效修饰疗法无法治疗PD。 GBA1突变引起的疾病很复杂影响多个器官。在动物模型中对GD和GBA1相关PD的忠实建模对于研究相关的疾病过程，并建立与临床相关的测试治疗模型方法。研究GBA1突变相关疾病的障碍是没有动物模型在多个器官中概括人类疾病的所有方面。以前开发了GBA1突变小鼠模型要么没有显示可检测的表型或影响受限的器官。他们的NGD和PD表型非常温和缺席的。我们最近的研究已将progranulin确定为GCASE的修饰符。 GBA1中删除progranulin 突变小鼠导致底物的积累，gaucher样巨噬细胞和肝脏，肺和脑器官的炎症，典型的GD表型。这个新型号（称为PG9V）开发的神经元表型概括了NGD和PD。我们的新PG9V模型克服了现有模型。我们假设通过尿素缺失对GBA1突变小鼠的遗传修饰影响内脏和中枢神经系统器官中的炎症和糖脂代谢，建立新型 GD和PD的临床上与临床相关的动物模型。我们将表征内脏GD表型（AIM 1）和评估PG9V小鼠模型中的CNS表型（AIM 2），以建立测试疗法的标准。此外，我们将测试SRT复合是否减轻PG9V小鼠中的疾病以确定PG9V模型的临床前值。这种新的GBA1突变相关的鼠标模型代表了现有鼠标的重大前进型号。 PG9V小鼠的全面表征将促进病理生理研究并启用在具有多个器官参与的单个模型中的治疗评估和毒性测试。