Modeling Progranulin hypomorphism for FTD in mice

描述（由申请人提供）：额颞叶痴呆（FTD）是仅次于阿尔茨海默病的第二种最常见的临床痴呆。FTD是由额颞皮质神经元变性引起的，导致这些脑区功能丧失。主要临床症状是难以根据社会需求改变行为，缺乏抑制，冲动和强迫行为，缺乏对他人的关心，个人卫生恶化和进行性语言功能障碍。它与阿尔茨海默病的不同之处在于，这种疾病开始时有轻度或无记忆丧失。只有到疾病的晚期，记忆力才会丧失。约40-50%的FTD病例有家族史，由基因突变引起。已确定突变导致FTD的基因为微管相关蛋白tau（MAPT）、带电多泡体蛋白2B（CHMP 2B）、含血管素蛋白（VCP）和颗粒蛋白前体（PGRN）。颗粒蛋白前体基因突变是最近发现的，已证明是FTD的常见遗传原因。与tau突变一起，它占家族性FTD病例的一半以上。遗传学研究表明，突变导致颗粒蛋白前体功能丧失，这种疾病是单倍不足的结果。为了研究疾病机制，我们建议应用新开发的转基因RNAi方法，通过使用诱导型miRNA表达构建体沉默颗粒蛋白前体基因来创建小鼠FTD模型。如果成功，我们将产生一种新的FTD动物模型，可用于研究神经退行性变机制和测试这种疾病的治疗策略。我们试图建立一个小鼠模型，额颞叶痴呆（FTD）的抑制颗粒蛋白前体表达使用RNAi。颗粒蛋白前体突变导致人类FTD，这是一种神经退行性疾病，改变人们的个性，计划能力和在社会环境中的适当行为。如果成功，我们的工作将建立这种疾病的第一个动物模型，可用于研究神经变性机制和测试治疗策略。

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is the 2nd most common clinical dementia after Alzheimer's disease. FTD results from neuronal degeneration in the frontal temporal cortices, leading to a loss of functions in these brain regions. The main clinical symptoms are difficulty in modifying behavior based on social demands, lack of inhibition, impulsive and compulsive acts, lack of concern for others, deterioration of personal hygiene and progressive language dysfunction. It differs from Alzheimer's disease in that the disease begins with mild or no memory loss. Only until the late stage of the disease does memory loss emerge. About 40-50% of FTD cases have a family history and are caused by genetic mutations. The genes whose mutation have been identified to cause FTD are microtubule-associated protein tau (MAPT), charged multivesicular body protein 2B (CHMP2B), vasolin-containing protein (VCP) and progranulin (PGRN). Mutations in progranulin gene are the most recently identified and have been shown to be a common genetic cause for FTD. Together with mutations in tau, it accounts more than half of the familial FTD cases. Genetic studies have implicated that the mutations cause loss of progranulin function and the disease is a result of haploinsufficiency. To study the disease mechanism, we propose to apply a newly developed transgenic RNAi approach to create a mouse FTD model by silencing the progranulin gene using an inducible miRNA-expressing construct. If successful, we will generate a new animal model for FTD, which can be used to investigate the neurodegeneration mechanism and test therapeutic strategies for this disease. We seek to establish a mouse model for frontotemporal dementia (FTD) by inhibition of progranulin expression using RNAi. Progranulin mutations cause human FTD, which is a neurodegenerative disease that changes people's personality, ability to plan and behave appropriately in social settings. If successful, our work will establish the first animal model for this disease, which can be used for studying neurodegeneration mechanisms and testing therapeutic strategies.