I2PP2A: A Therapeutic Target

描述(申请人提供)：阿尔茨海默病(AD)是老年人中最常见的痴呆症原因，占美国500多万例，中国中国600多万例，全球2000多万例。微管相关蛋白tau的异常过度磷酸化和脑内b-淀粉样蛋白的形成是AD的两个标志性病理过程。虽然tau过度磷酸化和抗体过度产生的机制已经被广泛研究，但目前还没有有效的治疗方法。到目前为止，仅旨在消除抗体的治疗临床试验一直令人失望。因此，研究同时抑制tau和Ab异常过度磷酸化的新靶点(S)值得研究。基于我们以前的研究，发现AD脑内蛋白磷酸酶2A(PP2A)的选择性降低，以及该酶的内源性蛋白抑制剂I1PP2A和I2PP2A参与了AD的发病机制，我们的长期目标是基于这一疾病机制开发一种有效的治疗AD神经退行性变的方法。这项为期三年的Fogarty国际研究合作奖(FIRCA)的具体目标是研究敲除抑制物-2(I2PP2A)是否是抑制tau/Ab病理和挽救明确定义的三重转基因AD小鼠模型(3xTgAD)的有价值的靶点。为此，我们提出了以下两个具体目标：(1)研究I2PP2A基因敲除是否可以抑制3xTgAD小鼠tau/神经纤维变性和b-淀粉样变性的异常过度磷酸化；(2)研究I2PP2A基因敲除是否可以抑制这些动物的神经退行性变和相关的认知功能障碍。这些研究将有助于验证AD药物开发的合理治疗目标，还将促进申请者在美国的实验室与外国合作者在中国的实验室之间的国际研究合作。这项研究将主要在武汉华中科技大学中国与王建志合作进行，作为国家卫生研究院批准号：R01 AG019158,2007年5月1日至2012年4月30日。FIRCA申请的目的是扩大美国实验室和国外合作者实验室的研究计划，以帮助阐明抑制I2PP2A是否可以恢复PP2A活性，挽救AD类型的组织病理学和认知，从而为AD药物的开发提供有效的治疗靶点。验证一个基于疾病的合理治疗目标，可以导致开发出一种或多种有效的治疗AD和相关疾病的药物，对美国和中华人民共和国中国来说都是高度相关和高度优先的。 与公共卫生相关：阿尔茨海默病(AD)及相关疾病，以异常过度磷酸化的tau蛋白的神经纤维变性为特征，是中老年痴呆的主要原因，在美国、中华人民共和国中国和世界范围内构成一个主要的公共卫生问题。FIRCA拨款申请的目的是通过联合研究I2PP2A作为治疗靶点的有效性，加强、扩大和扩大在这一全球健康问题上的国际研究合作。I2PP2A是一种调节tau磷酸化的蛋白磷酸酶(PP)-2A抑制剂。异常过度磷酸化的tau蛋白是神经原纤维缠结的主要蛋白质亚单位，神经原纤维缠结是阿尔茨海默病患者、成人唐氏综合症患者和相关牛磺酸疾病患者的标志性组织病理脑损伤。

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is the most common cause of dementia in the elderly, which accounts for over five million cases in the United States, six million in the P.R. China, and over 20 million cases worldwide. Abnormal hyperphosphorylation of the microtubule associated protein tau and formation of b-amyloid (Ab) in the brain are the two hallmark pathological processes in AD. Although the mechanisms underlying tau hyperphosphorylation and Ab overproduction have been extensively studied, there is currently no effective cure for this disease. The therapeutic clinical trials aimed at eliminating Ab alone have been disappointing, to date. Therefore, new target(s) to inhibit simultaneously abnormal hyperphosphorylation of tau and Ab overproduction warrant investigation. Based on our previous studies which showed a selective decrease in brain protein phosphatase 2A (PP2A) in AD brain and the involvement of the endogenous protein inhibitors, I1PP2A and I2PP2A, of this enzyme in the etiopathogenesis of AD, our long-term objective is to develop an effective treatment for AD neurodegeneration based on this disease mechanism. The specific objective of this three-year Fogarty International Research Collaboration Award (FIRCA) is to study whether knockdown of inhibitor-2 (I2PP2A) is a valuable target to inhibit tau/Ab pathologies and to rescue the memory deficit in a well-defined triple transgenic mouse model of AD (3xTgAD). Towards this goal, we propose the following two specific aims: (1) To study whether knockdown of I2PP2A can inhibit abnormal hyperphosphorylation of tau/neurofibrillary degeneration and b-amyloidosis in 3xTgAD mice; and (2) To study whether knockdown of I2PP2A can inhibit neurodegeneration and associated cognitive impairment in these animals. These studies will help validate a rational therapeutic target for drug development of AD, and will also foster international research collaboration between the applicant's laboratory in the United States and the Foreign Collaborator's laboratory in China. This research will be done primarily in Huazhong University of Science and Technology, Wuhan, P.R. China, in collaboration with Jian-Zhi Wang, as an extension of NIH Grant No. R01 AG019158, 5/1/2007 to 4/30/2012. The objective of this FIRCA application is to extend and expand the research programs of both the United States laboratory and the Foreign Collaborator's laboratory that will help elucidate whether inhibition of I2PP2A can restore PP2A activity and rescue AD-type histopathology and cognition, and thus to provide an effective therapeutic target for AD drug development. Validation of a disease-based rational therapeutic target that can lead to the development of one or more effective therapeutic drugs for AD and related disorders is highly relevant and a high priority both for the United States and for the P.R. China. PUBLIC HEALTH RELEVANCE: Alzheimer disease (AD) and related disorders, characterized by neurofibrillary degeneration of abnormally hyperphosphorylated tau, are the major causes of middle- to old-age dementia, and constitute a major public health problem in the United States, in the P.R. China, and worldwide. The objective of this FIRCA grant application is to enhance, extend, and expand international research collaboration on this global health problem by jointly investigating the validity of I2PP2A, an inhibitor protein phosphatase (PP) -2A that regulates the phosphorylation of tau, as a therapeutic target. The abnormally hyperphosphorylated tau protein is the major protein subunit of neurofibrillary tangles, a hallmark histopathological brain lesion of individuals with AD, adults with Down syndrome, and individuals with related tauopathies.