Modeling Progranulin hypomorphism for FTD in mice

描述(申请人提供)：额颞性痴呆(FTD)是仅次于阿尔茨海默病的第二种最常见的临床痴呆。FTD是由于额叶颞叶皮质神经元变性，导致这些脑区功能丧失所致。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，个人卫生状况恶化，进行性语言障碍。它与阿尔茨海默病的不同之处在于，这种疾病始于轻微的或没有记忆丧失。直到疾病的晚期，才会出现记忆力丧失。大约40%-50%的FTD病例有家族史，是由基因突变引起的。微管相关蛋白tau(MAPT)、带电多囊体蛋白2B(CHMP2B)、含血管脂蛋白(VCP)和原颗粒蛋白(PGRN)是引起FTD的基因。前颗粒蛋白基因突变是最近发现的，并已被证明是FTD的常见遗传原因。加上tau基因突变，占家族性FTD病例的一半以上。遗传学研究表明，突变会导致原颗粒蛋白功能丧失，而这种疾病是单倍体功能不足的结果。为了研究疾病机制，我们建议应用一种新开发的转基因RNAi方法来建立小鼠FTD模型，方法是使用可诱导的miRNA表达载体沉默原颗粒基因。如果成功，我们将建立一种新的FTD动物模型，可以用来研究这种疾病的神经退变机制和测试治疗策略。我们试图通过使用RNAi抑制前颗粒蛋白的表达来建立额颞叶痴呆(FTD)的小鼠模型。原颗粒突变会导致人类FTD，这是一种神经退行性疾病，会改变人们的个性、计划和在社会环境中适当行为的能力。如果成功，我们的工作将建立第一个这种疾病的动物模型，可以用于研究神经退行性变的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.