Modeling Progranulin hypomorphism for FTD in mice

描述（申请人提供）：额颞叶痴呆（FTD）是仅次于阿尔茨海默病的第二大常见临床痴呆。FTD是由额颞叶皮层的神经元退化引起的，导致这些大脑区域的功能丧失。主要临床症状为难以根据社会需求改变行为、缺乏抑制力、冲动和强迫行为、缺乏对他人的关心、个人卫生状况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，这种疾病始于轻微或没有记忆丧失。直到疾病的晚期才会出现记忆丧失。约40-50%的FTD病例有家族史，由基因突变引起。目前已确定引起FTD的突变基因有微管相关蛋白tau （MAPT）、带电多泡体蛋白2B （CHMP2B）、含血管球蛋白蛋白（VCP）和前颗粒蛋白（PGRN）。前颗粒蛋白基因的突变是最近发现的，并已被证明是FTD的常见遗传原因。加上tau基因的突变，它占了家族性FTD病例的一半以上。遗传学研究表明，突变导致前颗粒蛋白功能丧失，该疾病是单倍体功能不全的结果。为了研究这种疾病的发病机制，我们提出了一种新的转基因RNAi方法，通过诱导mirna表达构建物沉默前颗粒蛋白基因来建立小鼠FTD模型。如果成功，我们将产生一种新的FTD动物模型，可用于研究该疾病的神经退行性机制和测试治疗策略。我们试图通过RNAi抑制蛋白前表达来建立额颞叶痴呆（FTD）小鼠模型。蛋白前突变导致人类FTD，这是一种神经退行性疾病，会改变人的个性、计划能力和在社会环境中适当行为的能力。如果成功，我们的工作将建立该疾病的第一个动物模型，可用于研究神经退行性变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.