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

项目概要： 我们的目标是开发一种新的小鼠模型，用于研究多器官中GBA 1突变引起的疾病。 系统. GBA 1编码一种溶酶体葡糖脑苷脂酶（GCase），负责降解其 鞘糖脂底物。GBA 1基因突变破坏GCase功能并导致戈谢病（GD） 其在内脏或中枢神经系统（CNS）器官中呈现异质性疾病表型。典型 内脏型GD 1的表现包括肝脾肿大、贫血、血小板减少和骨质减少。 神经元病性GD（nGD、GD2和GD3）是导致死亡的快速进展性CNS疾病， 伴有内脏症状。GD影响与NIDDK研究使命一致的多个器官 （肝）、NHLBI（肺）、NINDS（CNS）和NIAMS（骨）。GBA1基因突变也是遗传风险， 帕金森病（Parkinson Disease，PD）已批准的疗法，底物减少疗法（SRT）和酶 替代疗法仅对伴有内脏症状的GD有效，不治疗CNS疾病。的 有效的疾病改善疗法不能用于治疗PD。GBA1突变引起的疾病是复杂的 影响多个器官在动物模型中对GD和GBA 1相关PD进行准确建模， 研究相关的疾病过程，并建立一个临床相关的模型，用于测试治疗 接近。研究GBA 1突变相关疾病的一个障碍是缺乏动物模型， 在多个器官中概括人类疾病的所有方面。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，要么影响有限的器官。他们的nGD和PD表型非常轻微， 无托叶我们最近的研究已经确定颗粒蛋白前体是GCase的修饰剂。Gba1中颗粒蛋白前体的缺失 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 发展了概括nGD和PD的神经元表型。我们的新型PG9V型号克服了 现有的模型。我们假设通过颗粒蛋白前体缺失对Gba1突变小鼠进行遗传修饰， 影响内脏和CNS器官的炎症和鞘糖脂代谢，建立了一种新的 GD和PD的临床相关动物模型。我们将描述内脏GD表型（目的1）， 在PG9V小鼠模型中评价CNS表型（目的2）以建立用于测试疗法的标准。此外，委员会认为， 我们将测试SRT化合物是否减轻PG9V小鼠的疾病以确定PG9V模型的临床前价值。 这种新的GBA 1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， 在涉及多个器官的单一模型中进行治疗评价和毒性测试。

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.