I2PP2A: A Therapeutic Target

I2PP2A：治疗靶点

• 批准号: 8148035
• 负责人: KHALID IQBAL
• 金额: $ 7.04万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8148035
• 关键词: Accounting; Adult; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Applications Grants; Award; Behavior; Biological; Brain; CREB1 gene; China; Cognition; Cognitive; Collaborations; Dementia; Dendritic Spines; Dependovirus; Deterioration; Development; Disease; Down Syndrome; Elderly; Electrophysiology (science); Elements; Enzymes; FOS gene; Fostering; Functional disorder; Genes; Goals; Grant; Hippocampus (Brain); Histopathology; Human; Impaired cognition; Individual; Injection of therapeutic agent; International; Investigation; Laboratories; Lead; Learning; Lesion; Measurement; Measures; Memory; Memory impairment; Microtubules; Modification; Molecular; Morphology; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Normal Cell; Nuclear Import; Pathologic Processes; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Preventive; Protein Subunits; Protein phosphatase; Proteins; Public Health; Research; Role; SET gene; Science; Senile Plaques; Senile dementia; Site; Small Interfering RNA; Solubility; Subfamily lentivirinae; Synapses; Synapsin I; Synaptophysin; Synaptosomes; Tauopathies; Technology; Testing; Tg2576; Therapeutic; Therapeutic Clinical Trial; Time; Transgenic Mice; Transgenic Organisms; United States; United States National Institutes of Health; Universities; Validation; Virus; abnormally phosphorylated tau; base; drug development; effective therapy; global health; improved; inhibitor/antagonist; morris water maze; mouse model; mutant; parent grant; presenilin-1; prevent; programs; restoration; secretase; synaptic function; tau Proteins; tau phosphorylation; therapeutic target; trafficking

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.

描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因，在美国有超过500万例，在中国有600万例。中国，全球超过2000万例。脑内微管相关蛋白tau的异常过度磷酸化和b-淀粉样蛋白（Ab）的形成是AD的两个标志性病理过程。虽然tau蛋白过度磷酸化和Ab过度产生的机制已被广泛研究，但目前还没有有效的治疗方法。迄今为止，旨在单独消除Ab的治疗性临床试验令人失望。因此，同时抑制tau和Ab过度产生的异常过度磷酸化的新靶标值得研究。基于我们先前的研究显示AD脑中脑蛋白磷酸酶2A（PP 2A）的选择性降低以及该酶的内源性蛋白抑制剂I1 PP 2A和I2 PP 2A在AD发病机制中的参与，我们的长期目标是基于该疾病机制开发有效的治疗AD神经变性的方法。这个为期三年的Fogarty国际研究合作奖（FIRCA）的具体目标是研究抑制剂-2（I2 PP 2A）的敲低是否是抑制tau/Ab病理学的有价值的靶点，并挽救明确定义的AD三重转基因小鼠模型（3xTgAD）中的记忆缺陷。为此，我们提出了以下两个具体目标：（1）研究敲低I2 PP 2A是否可以抑制3xTgAD小鼠中tau/神经元变性和b-淀粉样变性的异常过度磷酸化;（2）研究敲低I2 PP 2A是否可以抑制这些动物中的神经变性和相关的认知障碍。这些研究将有助于验证AD药物开发的合理治疗靶点，也将促进申请人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。本研究将主要在华中科技大学进行。中国，与Jian-Zhi Wang合作，作为NIH批准号R 01 AG 019158的扩展，2007年5月1日至2012年4月30日。该FIRCA申请的目的是扩展和扩展美国实验室和外国合作者实验室的研究项目，这将有助于阐明抑制I2 PP 2A是否可以恢复PP 2A活性并挽救AD型组织病理学和认知，从而为AD药物开发提供有效的治疗靶点。验证基于疾病的合理治疗靶点，可以导致开发一种或多种有效的AD和相关疾病治疗药物，这对美国和中国来说都是高度相关和高度优先的。中国 公共卫生关系：阿尔茨海默病（AD）和相关病症的特征在于异常过度磷酸化的tau的神经元变性，其是中老年痴呆的主要原因，并且在美国、在P.R.中国，乃至全世界。该FIRCA拨款申请的目的是通过共同研究I2 PP 2A（一种调节tau磷酸化的抑制剂蛋白磷酸酶（PP）-2A）作为治疗靶点的有效性，加强，扩展和扩大关于这一全球健康问题的国际研究合作。异常过度磷酸化的tau蛋白是神经元缠结的主要蛋白亚基，神经元缠结是AD个体、唐氏综合征成人和相关tau蛋白病个体的标志性组织病理学脑损伤。