YAP/TAZ in Schwann Cells as potential therapeutic targets in CMT1A and HNPP.

雪旺细胞中的 YAP/TAZ 作为 CMT1A 和 HNPP 的潜在治疗靶点。

基本信息

批准号：
10537511
负责人：
Seth Michael Moore
金额：
$ 3.23万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537511
关键词：
Ablation Age Alleles Animals Biochemical Biopsy Biopsy Specimen Cell Cycle Cell Differentiation process Cell Nucleus Cell Proliferation Cells Cellular biology Charcot-Marie-Tooth Disease Clinic Clinical Communication Complex Critical Thinking Cryoultramicrotomy Defect Demyelinations Development Disease EGR2 gene Elasticity Electrons Electrophysiology (science)Embryo Environment GTP-Binding Proteins Genes Genetic Genetic Transcription Glutaminase Goals Hereditary neuropathy with liability to pressure palsies Hospitals Human Immunohistochemistry Inherited Institutes Integrins Iowa Italy Knock-out Laminin Receptor Lipids Mechanics Mediating Microscopic Modeling Morphology Mus Myelin Nerve Nerve Fibers Neuroglia Neuropathy Nuclear PMP22 gene Pathologic Pathology Pathway interactions Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Permeability Phenotype Phosphorylation Phosphorylation Inhibition Phosphotransferases Physicians Physiology Prevalence Problem Solving Proteins Radial Regulation Research Resistance Role Sampling Schwann Cells Scientist Sensory Signal Pathway Skin Sorting - Cell Movement Source Tamoxifen Techniques Testing Therapeutic Time Training Transcription Coactivator Transcriptional Coactivator with PDZ-Binding Motif Transcriptional Regulation Tumor Suppressor Proteins Universities Western Blotting base behavioral phenotyping career conditional knockout congenic disease phenotype dosage experience experimental study improved mRNA Expression mechanical properties mechanical signal mechanical stimulus mouse model myelination neurophysiology novel novel therapeutics overexpression ranpirnase receptor response sciatic nerve skills skills training sural nerve therapeutic target transcription factor

项目摘要

Project Summary The heterogeneous group of inherited peripheral neuropathies referred to as Charcot-Marie Tooth disease, have an estimated prevalence of 1:25001. Among these disorders, Charcot Marie Tooth 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) are the most common1. These diseases result from duplication (CMT1A) or deletion (HNPP) of the gene encoding for peripheral myelin protein 22 (PMP22)2, leading to its over or underexpression in Schwann cells (SCs), respectively3,4. There are no cures for these debilitating diseases, highlighting the need to identify novel mechanisms to modulate PMP22 expression, and to elucidate the pathological mechanisms involved in peripheral nerve (PN) demyelination. Recently, the complex formed by the transcriptional coactivator with PDZ-binding motif (TAZ)5 and the transcription factor TEA domain 1 (TEAD1)6,7, was shown to positively regulate PMP22 expression8,9. Therefore, modulation of TAZ activation is an intriguing therapeutic avenue to decrease PMP22 transcription in CMT1A, or increase its transcription in HNPP. Moreover, the functions of PMP22 in SC biology include cell cycle regulation10,11, formation of cellular junctions and myelin permeability12,13, and determining the mechanical properties of myelinated PN fibers14,15. Notably, these aspects of SC biology are also regulated by TAZ, and the related transcriptional coactivator Yes- associated protein 1 (YAP)16–20; the major downstream effectors of the HIPPO pathway21,22. Activated YAP/TAZ translocate to the nucleus and associate with TEAD1-423,24, altering the transcription of many genes essential for SC proliferation and differentiation including laminin receptors, integrins, G-protein Ga, EGR2, and myelin and lipid genes8,20,25,26. Therefore, changes in the activation status of YAP/TAZ in CMT1A and HNPP may impact the physiology of SCs, contributing to demyelination. Thus, we hypothesize that modifying TAZ expression may restore proper PMP22 expression and ameliorate the phenotypes of CMT1A through direct regulation of PMP22. We also postulate that YAP/TAZ activation may be altered in mouse models and human samples of CMT1A and HNPP, potentially contributing to altered SC proliferation, myelin permeability, and mechanical properties of PNs. To determine the effects of modulating TAZ activation, genetic ablation of TAZ alleles in SCs of PMP22- overexpressing mice will be assessed for morphological, electrophysiological, sensory, and behavioral phenotypic rescue. The presence of altered YAP/TAZ activation will be assessed through immunostaining and biochemical analyses of human biopsy samples and mouse models of CMT1A and HNPP. The research for this proposed project will be conducted at the Institute for Myelin and Glia Exploration, composed of an interdisciplinary group of scientists dedicated to the study of myelin and its associated diseases. The overall training plan will emphasize the development of scientific communication skills, training in various techniques, improving critical thinking and problem-solving skills, as well as opportunities for regular clinical experiences. This will create the ideal environment for developing the skills necessary for a career as a physician-scientist.

项目摘要被称为charcot-marie牙齿疾病的异质遗传神经病的异质群估计的患病率为1：25001。在这些疾病中，Charcot Marie Tooth 1A（CMT1A）和世袭对压力麻痹（HNPP）责任的神经病是最常见的1。这些疾病是由外围髓磷脂蛋白22（PMP22）2的基因编码的重复（CMT1A）或缺失（HNPP），领先在雪旺细胞（SCS）中的过度或不渗透到3,4。这些使这些衰弱的治疗方法疾病，强调需要确定调节PMP22表达的新型机制并阐明涉及周围神经（PN）脱髓鞘的病理机制。最近，该复合物由带有PDZ结合基序（TAZ）5和转录因子茶域1的转录共激活因子1 （TEAD1）6,7，显示为正调节PMP22表达8,9。因此，TAZ激活的调节是一个有趣的治疗途径，可减少CMT1A中的PMP22转录，或增加其转录 HNPP。此外，PMP22在SC生物学中的功能包括细胞周期调节10,11，形成细胞连接和髓磷脂渗透率12,13，并确定骨髓PN纤维的机械性能14,15。值得注意的是，SC生物学的这些方面也受TAZ的调节，相关的转录共激活因子是 - 相关蛋白1（YAP）16–20;河马途径的主要下游效应21,22。激活的YAP/TAZ 转移到核并与TEAD1-423,24相关，改变了许多基因的转录用于SC增殖和分化，包括层粘连蛋白受体，整联蛋白，G蛋白GA，EGR2和髓磷脂和脂质基因8,20,25,26。因此，CMT1A和HNPP中YAP/TAZ的激活状态的变化可能会影响 SC的生理学，导致脱髓鞘。那我们假设修改TAZ表达可能通过直接调节PMP22来恢复正确的PMP22表达并改善CMT1A的表型。我们还假设，在CMT1A的小鼠模型和人类样品中，YAP/TAZ激活可能会改变 HNPP，有可能导致PNS的SC增殖，髓磷脂渗透性和机械性能的改变。为了确定调节TAZ激活的影响，在PMP22- sc中的TAZ等位基因的遗传消融过表达的小鼠将评估形态学，电生理，感觉和行为表型救援。 YAP/TAZ激活改变的存在将通过免疫染色和人类活检样品和CMT1A和HNPP的小鼠模型的生化分析。这项研究拟议的项目将在髓鞘和神经胶质研究所进行，由跨学科的科学家小组致力于研究髓磷脂及其相关疾病。总体培训计划将强调发展科学沟通技巧，各种技术培训，提高批判性思维和解决问题的技能，以及定期临床经验的机会。这将创造一个理想的环境，以发展作为身体科学家职业所必需的技能。