PTP1B Inhibitors for the Treatment of Rett Syndrome

拟议的研究旨在促进Rett新药物疗法的开发 综合征（RTT），一种严重的，目前无法治疗的神经发育障碍， 功能. RTT是一种复杂的疾病，影响约1/10，000的女性分娩，由以下原因引起： 编码甲基CpG结合蛋白2（MeCP 2）1，2，a的基因中的功能缺失突变 转录调节蛋白3.这一建议建立在唐克斯最近的发现基础上， PTPN 1，编码蛋白酪氨酸磷酸酶1B（PTP 1B）的基因，是一个转录因子， 在RTT患者和Mecp 2小鼠模型中上调。PTP 1B是一个关键的 一种调节多种信号通路的酶，在RTT中被破坏，包括蛋白酪氨酸 激酶TrkB，脑源性神经营养因子（BDNF）的高亲和力受体4。Katz的研究 和同事证明TrkB信号传导的缺陷与神经功能障碍有关， 在RTT小鼠模型中，TrkB磷酸化（活化）与症状有关 恢复5 -7.与这些结果一致，Tonks实验室证明，使用 为其他适应症开发的临床阶段分子，与TrkB活化增加相关 和其他底物，以及改善RTT小鼠的神经和代谢功能4。在一起， 这些发现突出了PTP 1B作为治疗RTT的高度有吸引力的靶点。因此 拟议的研究旨在评估两种结构和机制不同的能力， PTP 1B抑制剂可改善RTT小鼠模型的神经功能和结构性突触缺陷。 这些研究将采用临床相关的行为终点，以提高翻译潜力 我们的研究结果，并将在两个不同的Mecp 2突变小鼠品系中复制， 实验室，以提高我们的结果的严谨性和意义。我们还将确定下游 靶点受RTT小鼠异常PTP 1B信号传导的影响，不仅要了解机制 潜在的PTP 1B抑制剂的治疗潜力，但也确定潜在的新的治疗 目标的这些研究旨在为PTP 1B的治疗潜力提供新的见解 用于治疗RTT的抑制剂。此外，考虑到异常细胞信号在某些遗传过程中的作用， 自闭症的亚组，包括异常磷酸酶信号传导（即，PTEN），希望这些研究 将有助于开发针对自闭症谱系其他障碍的有效治疗方法 也

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.