PTP1B Inhibitors for the Treatment of Rett Syndrome

这项拟议的研究旨在促进Rett的新药物疗法的开发。 综合征(RTT)，一种严重的、目前无法治疗的自闭症神经发育障碍 功能。RTT是一种复杂的疾病，大约每10,000名女性新生儿中就有1人受到影响，由 甲基CpG结合蛋白2(MeCP2)1，2，a基因功能缺失突变 转录调节蛋白3.这一建议建立在唐克斯和戴维斯最近的发现之上 同事们认为，PTPN1，编码蛋白酪氨酸磷酸酶1B(PTP1B)的基因，是一种转录 MeCP2的靶标，在RTT患者和MeCP2小鼠模型中上调。PTP1B是一个关键 调节RTT中被破坏的多个信号通路的酶，包括蛋白质酪氨酸 脑源性神经营养因子的高亲和力受体--激酶TrkB--4.Katz的研究 和同事们证明了TrkB信号的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 追回5-7。与这些结果一致的是，Tonks实验室证明了使用 为其他适应症开发的临床阶段分子与TrkB的激活增加有关 和其他底物，以及改善了RTT小鼠的神经和代谢功能。一起， 这些发现强调了PTP1B是治疗RTT的一个非常有吸引力的靶点。因此， 拟议的研究旨在评估两个在结构和力学上截然不同的 PTP1B抑制剂改善RTT小鼠模型的神经功能和结构突触缺陷。 这些研究将利用临床上相关的行为终点来增强翻译潜力 并将在两个不同品系的MeCP2突变小鼠身上复制 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 PTP1B信号异常对RTT小鼠靶点的影响 潜在的PTP1B抑制剂的治疗潜力，但也确定潜在的新疗法 目标。这些研究旨在为PTP1B的治疗潜力提供新的见解 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 自闭症的亚群，包括磷酸酶信号异常(即PTEN)，希望这些研究 将有助于开发对自闭症谱系上的其他障碍的有效治疗 也是。

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.