I2PP2A: A Therapeutic Target

I2PP2A：治疗靶点

• 批准号: 8327738
• 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/8327738
• 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.

描述（由申请人提供）：阿尔茨海默病（AD）是老年人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，全球有超过 2000 万例。大脑中微管相关蛋白 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。尽管tau蛋白过度磷酸化和抗体过量产生的机制已被广泛研究，但目前尚无有效治愈这种疾病的方法。迄今为止，旨在单独消除抗体的治疗性临床试验令人失望。因此，同时抑制 tau 蛋白异常过度磷酸化和抗体过量产生的新靶标值得研究。我们之前的研究表明，AD 脑中脑蛋白磷酸酶 2A (PP2A) 选择性减少，并且该酶的内源性蛋白抑制剂 I1PP2A 和 I2PP2A 参与了 AD 的发病机制，我们的长期目标是根据这种疾病机制开发针对AD神经变性的有效治疗方法。这项为期三年的福格蒂国际研究合作奖 (FIRCA) 的具体目标是研究抑制剂 2 (I2PP2A) 的敲除是否是抑制 tau/Ab 病理学并挽救明确三联体中的记忆缺陷的有价值的靶点AD 转基因小鼠模型 (3xTgAD)。为了实现这一目标，我们提出以下两个具体目标：（1）研究I2PP2A的敲低是否可以抑制3xTgAD小鼠中tau/神经原纤维变性和b-淀粉样变性的异常过度磷酸化； (2) 研究 I2PP2A 的敲低是否可以抑制这些动物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，也将促进美国申请人实验室与中国外国合作者实验室之间的国际研究合作。这项研究将主要在中国武汉华中科技大学与王建志合作进行，作为 NIH 拨款号 R01 AG019158（2007 年 5 月 1 日至 2012 年 4 月 30 日）的延伸。本次 FIRCA 申请的目的是延伸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 I2PP2A 是否可以恢复 PP2A 活性并挽救 AD 型组织病理学和认知，从而提供AD药物开发的有效治疗靶点。验证基于疾病的合理治疗靶点，从而开发出一种或多种有效治疗阿尔茨海默病及相关疾病的药物，对于美国和中国来说都是高度相关和高度优先的。