Genetic and Genomic Analysis of Niemann Pick Type C1 disease

该项目的长期目标是确定尼曼-匹克C型（NP-C）疾病的遗传基础，研究其在疾病发病机制中的作用，并利用这些信息来帮助诊断和治疗这种疾病。NP-C是一种常染色体隐性遗传的神经内脏脂质储存障碍，表现为可变的肝脾肿大、垂直核上性眼肌麻痹、进行性共济失调、肌张力障碍和痴呆。我们小组长期致力于研究这种疾病的几个方面，包括涉及遗传诊断和治疗方法的方面。 通过多机构合作和Bench to Bedside奖，我们建立了一项自然史研究，以确定疾病预防的时间进程，识别生物标志物，并作为评估治疗干预措施的基础。在过去的几年里，我们已经广泛地分析了模型模型，以提供更多的见解的发病机制，使用基因表达分析。 我们一直在评估肝脏和大脑中基因表达的变化，以确定被破坏的途径。 在无症状的动物中，我们发现了涉及脂质代谢、参与花生四烯酸和药物代谢的细胞色素P450酶、炎症和免疫反应、丝裂原活化蛋白激酶和G蛋白信号传导、细胞周期调节、细胞粘附和细胞骨架重塑的基因的变化。相反，参与细胞凋亡和氧化应激的基因在晚期病理样品中出现变化。我们还使用这种分析来确定潜在的生物标志物，然后评估住院患者样本。 由此，我们已经鉴定了半乳糖凝集素-3（LGALS 3），一种促炎分子，和组织蛋白酶D（CTSD），一种溶酶体天冬氨酸蛋白酶。这两种蛋白质的血清水平升高与神经系统疾病的严重程度相关，并且似乎对NPC 1疾病具有特异性。 对于NCAT，我们已经启动了一项化合物筛选，以确定潜在的治疗模式，并在体外和体内进行了测试。我们还利用NIH主任挑战奖来协助全基因组siRNA筛选，以确定有助于遗传变异的修饰位点。我们现在正在开发常规和反义方法来模拟这种疾病的动物模型，以评估候选修饰剂途径和评估已确定的治疗干预措施。

The long term goal of this project is to identify the genetic basis responsible for Niemann-Pick Type C (NP-C) disease, to study its role in the pathogenesis of the disorder and to use this information to aid in the diagnosis and treatment of this disease. NP-C is an autosomal- recessive, neurovisceral lipid storage disorder and presents as variable hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia. Our group has a long term commitment to studying several aspects of this disease including those involving genetic diagnostic and therapeutic approaches. Through a multi-institute collaboration and a Bench to Bedside award we have established a natural history study in order to determine the time course of disease prevention, identification of biomarkers and as a basis for assessment of therapeutic interventions. Over the last years we have extensively analysed the model model to provide additional insights into the pathogensisi using gene expression analyses. We have been assessing changes in gene expression in the liver and brain to identify pathways that are disrupted. In asymptomatic animals we found changes in genes involving lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, genes involved in apoptosis and oxidative stress appeared to change in late pathological samples. We have also used this analysis to identify potential biomarkers that we then assess inpatient samples. From this we have identified galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1 disease. With NCATs we have initiated a compound screen to identify potential treatment paradigms and have been testing them in vitro and in vivo. We are also using an NIH Directors Challenge award to assist in a whole genome siRNA screen to identify modify loci that contribute to the genetic variation. We are now developing conventional and antisense approaches to mimic animal models of this disease to assess candidate modifier pathways and to assess identified therapeutic interventions.