Laminin receptors and signals in Schwann cells

雪旺细胞中的层粘连蛋白受体和信号

• 批准号: 9914380
• 负责人: M. Laura Feltri
• 金额: $ 40.5万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9914380
• 关键词: Axon; Binding; Biological Assay; Biopsy; Cadherins; Cell Communication; Cell Differentiation process; Cell Nucleus; Cells; Cellular biology; Charcot-Marie-Tooth Disease; Complex; Data; Deformity; Demyelinating Diseases; Development; Disease; EGR2 gene; Extracellular Matrix; Failure; Funding; Gene Dosage; Gene Expression; Genetic; Goals; Grant; Hereditary Motor and Sensory Neuropathy Type I; Hereditary neuropathy with liability to pressure palsies; Human; Joints; Laboratories; Laminin; Laminin Receptor; Libraries; Luciferases; Measures; Mechanics; Mediating; Mediator of activation protein; Modeling; Mus; Muscle Weakness; Muscular Atrophy; Myelin; Neuropathy; PMP22 gene; Pain; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phenotype; Proteins; Rattus; Receptor Signaling; Research; Role; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; System; Testing; Work; base; cell behavior; cell type; disability; disabling symptom; dosage; extracellular; improved; in vivo; member; mutant; myelination; novel; overexpression; repaired; small hairpin RNA; transcription factor

Peripheral neuropathies are a common cause of disability and have no cure. The extracellular signals that drive Schwann cell differentiation are important for peripheral nervous system myelination and are potentially accessible to improve failure in certain human peripheral neuropathies. In previous grant cycles, my laboratory identified essential Schwann cell signaling pathways that are modulated by LAMININS in the extracellular matrix. Among them, RAC1, a small-RhoGTPase and YAP and TAZ, effectors of the HIPPO pathway, are essential for normal Schwann cell development. The proposed research will characterize how RAC1 and the HIPPO pathway intersect and identify novel components of these pathways. The novel components include STRIATIN3 and MOB4, members of the STRIPAK complex that we identified as novel RAC1 interactors, and the atypical cadherin CELSR2, a putative mediator of Schwann cell-axon interactions. Preliminary data show that STRIATIN3 and CELSR2 may be important for myelination. Furthermore, this research will identify upstream regulators of the HIPPO pathway in Schwann cells using unbiased approaches. YAP and TAZ may also modulate human neuropathies by mediating mechanical signals and by controlling the expression of genes such as Peripheral Myelin Protein 22 (PMP22), whose altered gene dosage causes 80% of Charcot-Marie-Tooth disease (CMT) cases. To determine if YAP and TAZ modulate PMP22 expression in the context of CMT, YAP and TAZ mutants will be crossed with CMT1 models to determine if PMP22 expression and the consequent phenotypes are modulated. This work will reveal novel fundamental regulators of two important signaling pathways in Schwann cells. As the function of RAC1 and the HIPPO pathway is conserved in different cell types, this work will elucidate novel aspects of cell biology, in addition to myelination, and may reveal ways to modulate signaling pathways relevant in human neuropathies.

周围神经病是导致残疾的常见原因，无法治愈。细胞外信号 促进雪旺细胞分化对周围神经系统髓鞘形成很重要 潜在地可用于改善某些人类周围神经疾病的失败。在以前的拨款中 周期，我的实验室发现了基本的雪旺细胞信号通路，这些信号通路是由 细胞外基质中的层粘连蛋白。其中，RAC1，一个小的RhoGTP酶和YAP和TAZ， 河马途径的效应器，对于正常的雪旺细胞发育是必不可少的。建议数 研究将表征RAC1和河马途径如何相交并识别新的成分 这些小路中。新的成分包括STRIPAK的成员STRIATIN3和MOB4 我们确定为新的RAC1相互作用因子的复合体，以及非典型的钙粘蛋白CELSR2，推测 雪旺细胞-轴突相互作用的中介物。初步数据显示，STRIATIN3和CELSR2可能 对髓鞘形成很重要。此外，这项研究将确定河马的上游调节因子 使用无偏倚的方法研究雪旺细胞中的通路。YAP和TAZ也可能调节人类 通过调节机械信号和控制基因的表达，如 外周髓鞘蛋白22(PMP22)，其改变的基因剂量导致80%的夏科-玛丽-牙 疾病(CMT)病例。要确定YAP和TAZ是否调节PMP22的表达 CMT、YAP和TAZ突变体将与CMT1模型杂交，以确定PMP22的表达和 随之而来的表型是调制的。这项工作将揭示两个新的基本调节器 雪旺细胞中的重要信号通路。因为RAC1和河马途径的功能是 在不同的细胞类型中保守，这项工作将阐明细胞生物学的新方面，除了 髓鞘形成，并可能揭示调节与人类神经疾病相关的信号通路的方法。