STEP inhibitors for intervention in Alzheimer's Disease

STEP 抑制剂干预阿尔茨海默病

基本信息

批准号：
8306030
负责人：
Lutz Tautz
金额：
$ 4.88万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2011-07-22 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306030
关键词：
AMPA Receptors Ablation Alzheimer&apos s Disease Amyloid beta-Protein Animal Model Antibodies Attenuated Autoimmune Diseases Biological Assay Brain Cell membrane Cells Chemicals Cognitive Collaborations Complex Corpus striatum structure Data Development Diabetes Mellitus Disease Enzymes Equilibrium Extracellular Domain Failure Functional disorder Generations GluR2 subunit AMPA receptor Glutamate Receptor Goals Hand Health Hippocampus (Brain)Human Injection of therapeutic agent Intervention Knockout Mice Lead Letters Libraries Malignant Neoplasms Mediating Membrane Memory Modeling Mus N-Methyl-D-Aspartate Receptors NR1 gene Neurodegenerative Disorders Neurons Patients Phase III Clinical Trials Phosphoric Monoester Hydrolases Phosphorylation Prefrontal Cortex Process Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Rattus Regulation Running Screening procedure Slice Structure Surface Synapses Synaptic plasticity Testing Therapeutic Time Tissues Transgenic Organisms Tyrosine Phosphorylation Western Blotting Work base cognitive function counterscreen cytotoxicity gamma secretase genetic manipulation high throughput screening human disease immunocytochemistry improved in vitro Assay in vivo inhibitor/antagonist milligram mouse model multicatalytic endopeptidase complex phosphatase inhibitor small molecule small molecule libraries synaptic function trafficking

项目摘要

DESCRIPTION (provided by applicant): Disturbance of the dynamic balance between protein tyrosine phosphorylation and dephosphorylation is crucial for the development of many serious conditions, including cancer, diabetes, and autoimmune disorders. This is the first time that tyrosine phosphatase inhibitors are being proposed to improve cognitive function in Alzheimer's disease (AD). STriatal-Enriched Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that is highly expressed in regions where consolidation of memory occurs and regulates the internalization of NMDARs. Our recent work demonstrates that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Moreover, using genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model, we showed that a decrease in STEP levels attenuates the cognitive and cellular deficits observed in six-month old 3xTg-AD mice. The hypothesis that STEP inhibitors may prove therapeutic for the treatment of AD is a shift in the current paradigm of reducing Abeta levels to inhibiting a downstream target of Abeta. The recent failure of the gamma-secretase inhibitor semagacestat in phase III clinical trials suggests that other approaches are clearly needed. This proposal seeks to generate the first STEP-specific inhibitors. Besides a screening ready HTS assay, we also have a secondary assay, profiling assays, as well as cell-based and in vivo assays in place to verify, characterize, and prioritize hits. We have milligram amounts of highly pure STEP in hand, so that HTS for STEP inhibitors could commence immediately.

描述（由申请人提供）：蛋白质酪氨酸磷酸化和去磷酸化之间动态平衡的干扰对于许多严重疾病的发展至关重要，包括癌症，糖尿病和自身免疫性疾病。这是第一次提出酪氨酸磷酸酶抑制剂来改善阿尔茨海默氏病（AD）的认知功能。富含纹状体的磷酸酶（步骤）是一种脑特异性蛋白酪氨酸磷酸酶，在发生记忆的巩固并调节NMDAR的内在化的区域中高度表达。我们最近的工作表明，在人类AD患者的前额叶皮层和AD动物模型中，步骤升高。此外，使用遗传操纵来减少三重转基因AD小鼠模型中的步骤活性，我们表明，步骤水平的降低会减少六个月大的3xTG-AD小鼠中观察到的认知和细胞缺陷。阶跃抑制剂可能证明用于治疗AD的假设是当前降低Abeta水平以抑制Abeta的下游靶标的范围的变化。在第三阶段临床试验中，γ-分泌酶抑制剂semagacestat的最新失败表明，显然需要其他方法。该提议旨在产生第一个特定的抑制剂。除了筛选准备的HTS测定法之外，我们还进行了辅助测定，分析测定，以及基于细胞的基于细胞的和体内测定，以验证，表征和优先级命中。我们手头上有毫克的高度纯净的步骤，因此用于步骤抑制剂的HT可以立即开始。