PTP1B Inhibitors for the Treatment of Rett Syndrome

用于治疗 Rett 综合征的 PTP1B 抑制剂

基本信息

批准号：
9562137
负责人：
David M. Katz
金额：
$ 20.44万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-08 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9562137
关键词：
Abnormal Cell Active Sites Address Affect Affinity Animals Antibodies Autistic Disorder Behavioral Biochemical Birth Brain Clinical Clinical Trials Cognitive Complex Confocal Microscopy Data Defect Dendritic Spines Development Disease Disease model Dose Drug Modelings Enzymes Female Fostering Foundations Genes Genetic Genetic Transcription Goals Image Individual Laboratories Metabolic Methyl-CpG-Binding Protein 2 Modeling Morphology Motor Mouse Strains Mus Mutant Strains Mice Nervous System Physiology Neurodevelopmental Disorder Neurologic Neurologic Dysfunctions Neurotrophic Tyrosine Kinase Receptor Type 2 PTEN gene PTPN1 gene Patients Pharmacology Pharmacotherapy Phenotype Phosphoric Monoester Hydrolases Phosphorylation Platelet Factor 4 Play Protein Inhibition Protein Tyrosine Kinase Protocols documentation Regimen Research Respiratory physiology Rett Syndrome Role Sampling Series Signal Pathway Signal Transduction Subgroup Symptoms Synapses Therapeutic Treatment Protocols Tyrosine Phosphorylation Vertebral column blood glucose regulation clinical development clinically relevant cognitive function comparative efficacy density design effective therapy experimental study hippocampal pyramidal neuron improved indexing inhibitor/antagonist insight long term memory loss of function mutation mouse model mutant new therapeutic target novel therapeutics optimal treatments phosphoproteomics pre-clinical promoter protein tyrosine phosphatase 1B respiratory targeted treatment therapy development treatment effect

项目摘要

The proposed research is designed to foster development of new pharmacological therapies for Rett syndrome (RTT), a severe and currently untreatable neurodevelopmental disorder with autistic features. RTT is a complex disorder affecting approximately 1 in 10,000 female births and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2)1,2, a transcriptional regulatory protein3. This proposal builds upon the recent discovery by Tonks and colleagues that PTPN1, the gene encoding protein tyrosine phosphatase 1B (PTP1B), is a transcriptional target of MeCP2 and is upregulated in RTT patients and Mecp2 mouse models. PTP1B is a critical enzyme that regulates multiple signaling pathways disrupted in RTT, including the protein tyrosine kinase TrkB, the high-affinity receptor for Brain Derived Neurotrophic Factor (BDNF)4. Studies by Katz and colleagues demonstrated that deficits in TrkB signaling are associated with neurologic dysfunction in RTT mouse models and that phosphorylation (activation) of TrkB is associated with symptom recovery5-7. Consistent with these results, the Tonks lab demonstrated that inhibition of PTP1B, using clinical stage molecules developed for other indications, is associated with increased activation of TrkB and other substrates, as well as improved neurological and metabolic function in RTT mice4. Together, these findings highlight PTP1B as a highly attractive target for the treatment of RTT. Therefore, the proposed studies are designed to evaluate the ability of two structurally and mechanistically distinct PTP1B inhibitors to improve neurologic function and structural synaptic defects in RTT mouse models. These studies will employ clinically relevant behavioral endpoints to enhance the translational potential of our findings and will be replicated in 2 different strains of Mecp2 mutant mice in two different laboratories to enhance the rigor and significance of our results. We will also identify downstream targets impacted by abnormal PTP1B signaling in RTT mice, not only to understand mechanisms underlying the therapeutic potential of PTP1B inhibitors but to also identify potential new therapeutic targets. These studies are designed to provide new insight into the therapeutic potential of PTP1B inhibitors for the treatment of RTT. Moreover, given the role of abnormal cell signaling in some genetic subgroups of autism, including abnormal phosphatase signaling (i.e., PTEN), it is hoped these studies will contribute to the development of effective treatments for other disorders on the autism spectrum as well.

拟议的研究旨在促进 Rett 新药理疗法的开发综合症（RTT），一种严重且目前无法治疗的自闭症神经发育障碍特征。 RTT 是一种复杂的疾病，影响大约万分之一的女性新生儿，由以下原因引起：编码甲基 CpG 结合蛋白 2 (MeCP2)1,2, a 的基因发生功能丧失突变转录调节蛋白3.该提议建立在唐克斯和同事们认为 PTPN1，编码蛋白酪氨酸磷酸酶 1B (PTP1B) 的基因，是一个转录 MeCP2 的靶点，并且在 RTT 患者和 Mecp2 小鼠模型中表达上调。 PTP1B 是一个关键调节 RTT 中被破坏的多种信号通路的酶，包括蛋白质酪氨酸激酶 TrkB，脑源性神经营养因子 (BDNF)4 的高亲和力受体。卡茨的研究和同事证明 TrkB 信号传导缺陷与神经功能障碍有关在 RTT 小鼠模型中，TrkB 磷酸化（激活）与症状相关恢复5-7。与这些结果一致，Tonks 实验室证明，使用 PTP1B 可以抑制 PTP1B 为其他适应症开发的临床阶段分子，与 TrkB 激活增加相关和其他底物，以及改善 RTT 小鼠的神经和代谢功能4。一起，这些发现强调 PTP1B 是治疗 RTT 的一个极具吸引力的靶点。因此，拟议的研究旨在评估两种结构和机制不同的能力 PTP1B 抑制剂可改善 RTT 小鼠模型的神经功能和结构突触缺陷。这些研究将采用临床相关的行为终点来增强转化潜力我们的发现并将在两种不同的 Mecp2 突变小鼠品系中进行复制实验室，以提高我们结果的严谨性和重要性。我们还将确定下游 RTT 小鼠中受异常 PTP1B 信号传导影响的靶点，不仅是为了了解机制揭示 PTP1B 抑制剂的治疗潜力，同时也确定潜在的新治疗方法目标。这些研究旨在为 PTP1B 的治疗潜力提供新的见解用于治疗RTT的抑制剂。此外，鉴于异常细胞信号传导在某些遗传中的作用自闭症亚组，包括异常磷酸酶信号传导（即 PTEN），希望这些研究将有助于开发自闭症谱系其他疾病的有效治疗方法以及。