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

项目总结： 我们的目标是建立一种新的小鼠模型来研究由多个器官的GBA1突变引起的疾病 系统。GBA1编码与其降解有关的溶酶体葡萄糖脑苷酶(GCase) 鞘糖脂底物。GBA1基因突变破坏GCase功能并导致高谢病(GD) 在内脏或中枢神经系统(CNS)器官中表现出不同的疾病表型。典型 内脏类型Gd1的表现包括肝脾肿大、贫血、血小板减少和骨量减少。 神经病理性GD(NGD、GD2和GD3)是一种进展迅速的中枢神经系统疾病，可导致死亡和 伴有内脏症状。GD影响多个器官，与NIDDK的研究使命一致 (肝脏)、NHLBI(肺)、NINDS(中枢神经系统)和NIAMS(骨)。GBA1基因突变也是糖尿病的遗传风险 发展中的帕金森病(PD)。已批准的治疗方法：底物减少疗法(SRT)和酶疗法 替代疗法，仅对有内脏症状的GD有效，不治疗中枢神经系统疾病。这个 目前尚无有效的疾病修正疗法来治疗帕金森病。GBA1突变引起的疾病是复杂的 影响到多个器官。在动物模型中忠实地建立GD和GBA1相关PD的模型对于 研究相关疾病的过程，并建立临床相关的模型来测试治疗 接近了。研究GBA1突变相关疾病的一个障碍是缺乏能够 概括了人类疾病在多个器官中的所有方面。先前开发的Gba1突变小鼠模型 要么没有表现出可检测到的表型，要么影响到受限的器官。他们的NGD和PD表型非常轻微到 缺席。我们最近的研究发现原颗粒蛋白是GCase的修饰物。Gba1中原颗粒蛋白的缺失 突变小鼠导致底物积累快速进展，高雪样巨噬细胞和 肝脏、肺和脑器官的炎症，是典型的GD表型。这种新型号(称为PG9V)还 发展出具有NGD和PD特征的神经元表型。我们的新PG9V型号克服了 现有的模型。我们推测Gba1基因突变小鼠通过原颗粒缺失进行遗传修饰 影响内脏和中枢器官的炎症和鞘糖脂代谢，建立了一种新的 临床相关的GD和PD动物模型。我们将描述内脏的GD表型(目标1)和 评估PG9V小鼠模型的中枢神经系统表型(AIM 2)，以建立测试治疗的标准。此外， 我们将测试SRT复方是否能减轻PG9V小鼠的疾病，以确定PG9V模型的临床前价值。 这种新的与GBA1突变相关的小鼠模型代表着现有小鼠的重大进步 模特们。PG9V小鼠的全面特征将有助于病理生理研究，并使 多器官受累的单一模型的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.