I2PP2A: A Therapeutic Target

I2PP2A：治疗靶点

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：阿尔茨海默氏病（AD）是老年人痴呆症最常见的原因，在美国占500万例，在中国下午600万例，全球超过2000万病例。微管相关蛋白tau的异常高磷酸化和大脑中B-淀粉样蛋白（AB）的形成是AD中的两个标志性病理过程。尽管已经对TAU高磷酸化和AB生产过量的机制进行了广泛的研究，但目前尚无对该疾病的有效治愈方法。迄今为止，旨在消除AB的治疗临床试验令人失望。因此，新的靶标可抑制tau和ab生产过量的同时抑制异常的过度磷酸化。基于我们先前的研究，该研究表明，AD大脑中脑蛋白磷酸酶2a（PP2A）的选择性降低以及该酶在AD的病原体中的内源性蛋白抑制剂，I1PP2A和I2PP2A的参与，我们的长期目标是为基于AD神经疾病的有效治疗而在AD的疗法中进行治疗。这项为期三年的Fogarty国际研究合作奖（FIRCA）的具体目标是研究抑制剂2（I2PP2A）的敲低是否是抑制TAU/AB病理学的宝贵目标，并在AD的良好定义的三重转基因小鼠模型（3XTXTGAD）中挽救了记忆不足。为了实现这一目标，我们提出以下两个具体目的：（1）研究I2PP2A的敲低是否可以抑制3xTGAD小鼠中Tau/神经原纤维退化和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标，还将促进美国申请人实验室与中国外国合作者的实验室之间的国际研究合作。这项研究将主要在中国P.R. Wuhan的Huazhong科学技术大学进行，作为NIH赠款No. R01 AG019158，5/1/2007年至4/30/2012的NIH赠款。该FIRCA应用的目的是扩展和扩展美国实验室和外国合作者的实验室的研究计划，这将有助于阐明抑制I2PP2A是否可以恢复PP2A活动并营救AD-ty-ty-type组织病理学和认知，从而为AD AD药物开发提供有效的治疗目标。验证基于疾病的理性治疗靶标，该靶标可能会导致一种或更有效的AD和相关疾病的治疗药物开发，对于美国和中国P.R. 公共卫生相关性：阿尔茨海默氏病（AD）和相关疾病，其特征是异常的高磷酸化tau神经纤维纤维退化，是中年至老年痴呆症的主要原因，构成了美国，中国和世界各地的美国的主要公共卫生问题。该FIRCA赠款应用的目的是通过共同研究I2PP2A的有效性，这是一种抑制剂蛋白磷酸酶（PP）-2a，以调节TAU的磷酸化，以增强，扩展和扩大有关该全球健康问题的国际研究合作。异常的高磷酸化tau蛋白是神经原纤维缠结的主要蛋白亚基，这是AD患者，患有唐氏综合症的成年人和患有相关tauopathies的个体的标志性组织病理学脑病变。