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PTPRD ligands for stimulant and opiate use disorders

用于兴奋剂和阿片类药物使用障碍的 PTPRD 配体

基本信息

批准号：
10120215
负责人：
George Richard Uhl
金额：
$ 31.51万
依托单位：
BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10120215
关键词：
3xTg-AD mouse Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Autopsy Basal Nucleus of Meynert Brain CDK5 gene Caenorhabditis elegans Cells Cerebral cortex Cerebrum Clinical Copy Number Polymorphism Cyclin-Dependent Kinases Cyclins Dementia Elements Enzymes Functional disorder Funding Future Genes Glycogen (Starch) Synthase Glycogen Synthase Kinases Haplotypes Homologous Gene Homozygote Human Human Genetics Hydrolysis In Vitro Introns Knock-out Knockout Mice Lead Ligands Link Messenger RNA Minor Modeling Mus National Institute of Drug Abuse Neurofibrillary Tangles Neurons Orthophosphate Pathologic Pathology Pathway interactions Peptides Pharmaceutical Preparations Pharmacology Phosphopeptides Phosphoproteins Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Phosphotyrosine Pilot Projects Play Positioning Attribute Property Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteomics Reagent Regulation Reporting Rewards Rodent Role Single Nucleotide Polymorphism Solid Specificity Synaptosomes Test Result Testing Thalamic structure Tyrosine Tyrosine Phosphorylation Validation Vanadates Ventral Tegmental Area Wild Type Mouse Work abnormally phosphorylated tau cholinergic neuron cognitive testing density experimental study genetic association genome-wide genomic biomarker hyperphosphorylated tau in vivo innovation insight mRNA Expression mutant neurofibrillary tangle formation new therapeutic target novel novel therapeutics opioid use disorder parent grant phosphatase inhibitor positive allosteric modulator prion-like receptor stimulant use tau Proteins tau mutation tau phosphorylation tau-1 transcriptome sequencing transgenic model of alzheimer disease

项目摘要

Pathological tau hyperphosphorylation and neurofibrillary pathology are major Alzheimer's disease (AD) pathophysiological elements that correlate with clinical dementia. Activities of several kinases that hyperphosphorylate tau, including cyclin dependent CDK5, glycogen synthase GSK3α and GSK3β are enhanced by phosphorylation of their own tyrosines (pY15, pY279 and pY216). Tyrosine kinases that phosphorylate and activate these three tau-phosphorylating kinases are known. However, the tyrosine phosphatase(s) that dephosphorylate and thus reduce activities of brain CDK5, GSK3α and GSK3β have not been reported. Several lines of evidence now support PTPRD, a receptor type protein tyrosine phosphatase, as a major contributor to dephosphorylating tau-phosphorylating enzymes including CDK5, GSK3α and GSK3β. We will test the hypothesis that PTPRD contributes to regulation of CDK5, GSK3α and GSK3β activities in ways that make PTPRD a novel, multifactorial, druggable contributor to tau pathophysiology in AD. We are fortunate that work developing a PTPRD phosphatase inhibitor to reduce reward from addictive substances is funded by a NIDA parent grant U01DA047713 that provides an exceptionally solid platform for the current supplement proposal. In vitro, we will test activities of CDK5, GSK3α and GSK3β wildtype, mutant and control/comparison phosphopeptides at wildtype/mutant human D1 and D1 + D2 phosphatase domains from PTPRD and other tyrosine phosphatases. We will seek potent interactions between wildtype PTPRD phosphatase and pY15 CDK5, pY279 GSK3α and/or pY216 GSK3β phosphopeptides vs lower potency interactions with dephosphorylated/mutant/control peptides, PTPRD mutants and other tyrosine phosphatases. In vivo, we will characterize effects of genetically or pharmacologically altered PTPRD activity on brain CDK5, GSK3α and GSK3β tyrosine phosphorylation in mice. In pilot projects, we will a) cross 3xTg-AD mice with PTPRD knockouts to seek suitability of these “4xTg-AD” mice for studies of effects on tau pathology in aging and b) synthesize and model NF504, NF506 and other potential positive allosteric modulators of PTPRD's phosphatase for future tests of our innovative hypotheses. This work will aid new understanding of Alzheimer's disease neurofibrillary pathology and help to define PTPRD as a novel therapeutic target.

病理性tau蛋白过度磷酸化和神经病理学是阿尔茨海默病（AD）的主要病理学特征与临床痴呆相关的病理生理学因素。几种激酶的活性，过度磷酸化tau蛋白，包括细胞周期蛋白依赖性CDK 5、糖原合酶GSK 3 α和GSK 3 β，通过其自身酪氨酸（pY 15、pY 279和pY 216）的磷酸化增强。的酪氨酸激酶磷酸化和激活这三种tau-磷酸化激酶是已知的。然而，酪氨酸去磷酸化并因此降低脑CDK 5、GSK 3 α和GSK 3 β活性的磷酸酶被举报。现在有几条证据支持PTPRD，一种受体型蛋白酪氨酸磷酸酶，作为脱磷酸化tau-磷酸化酶的主要贡献者，包括 CDK5、GSK 3 α和GSK 3 β。我们将检验PTPRD有助于调节CDK 5、GSK 3 α和GSK 3 β活性的假设以使PTPRD成为AD中tau病理生理学的新的、多因素的、可药物化的贡献者的方式。幸运的是，我们正在开发一种PTPRD磷酸酶抑制剂，物质由NIDA母基金U 01 DA 047713资助，该基金为以下项目提供了非常坚实的平台：目前的补充方案。在体外，我们将测试CDK 5、GSK 3 α和GSK 3 β野生型、突变型在野生型/突变型人D1和D1 + D2磷酸酶结构域的对照/比较磷酸肽 PTPRD和其他酪氨酸磷酸酶。我们将寻找野生型PTPRD之间的有效相互作用，磷酸酶和pY 15 CDK 5、pY 279 GSK 3 α和/或pY 216 GSK 3 β磷酸肽与较低效力与去磷酸化/突变/对照肽、PTPRD突变体和其它酪氨酸磷酸酶的相互作用。在体内，我们将表征遗传或药理学改变的PTPRD活性对脑CDK 5的影响，小鼠中的GSK 3 α和GSK 3 β酪氨酸磷酸化。在试点项目中，我们将a）将3xTg-AD小鼠与 PTPRD敲除，以寻求这些“4xTg-AD”小鼠对衰老中tau病理学影响的研究的适用性和B）合成和模拟NF 504、NF 506和PTPRD的其它潜在的正变构调节剂磷酸酶，用于我们创新假设的未来测试。这项工作将有助于对阿尔茨海默氏症的新认识疾病神经病理学和帮助定义PTPRD作为一个新的治疗靶点。