Impact of Schwann Cell Pathology on Axon Structure and Function

雪旺细胞病理学对轴突结构和功能的影响

基本信息

批准号：
10568051
负责人：
JAMES SALZER
金额：
$ 57.21万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10568051
关键词：
Action Potentials Affect Age Months Axon Basal lamina Biology Cell Nucleus Charcot-Marie-Tooth Disease Clinical Collagen Cyclic AMP Defect Diameter Disease Distal EGR2 gene Exhibits Failure Fiber G-Protein-Coupled Receptors Genetic Transcription Human Inflammation Inflammatory Response Inherited Laminin Receptor Longevity Macrophage Maintenance Minor Mus Mutant Strains Mice Mutation Myelin Myelin Sheath Nerve Nervous System Physiology Neural Conduction Neurologic Neuropathy Paralysed Pathogenesis Pathologic Pathology Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phenotype Population Proteins Radial Ranvier&apos s Nodes Regulation Role Schwann Cells Series Severities Signal Transduction Structure Testing Thick cellular pathology clinical phenotype conditional knockout differential expression disability dysmyelination inflammatory milieu insight mouse model mutant myelination nerve injury neuroinflammation neurotransmission novel therapeutic intervention pharmacologic sciatic nerve transcription factor transcriptome transcriptome sequencing

项目摘要

Reciprocal interactions between axons and Schwann cells (SCs) drive the formation, function, and maintenance of myelinated nerves, which are essential for effective saltatory conduction and neurologic function. Extrinsic signals from the axon and the basal lamina (BL) cooperatively drive expression of a series of SC transcription factors (TFs), culminating in the expression of Egr2, the master regulator of PNS myelination. Egr2 is required for SCs to advance from the promyelinating stage, when they wrap axons once, to myelination, when they upregulate myelin components and form the multilamellar myelin sheath. Myelinating SCs in turn re-organize axons into distinct domains, in particular the node of Ranvier, and increase axon size. These collective changes enable and optimize action potential propagation by saltatory conduction. The importance of this regulation of axon biology by SCs is underscored by the disability associated with acquired and inherited (e.g., Charcot Marie Tooth (CMT) disorders of myelinating SCs (mSCs). CMTs that result from various SC mutations cause de/dysmyelination characterized by slow nerve conduction velocity (NCV), often with nerve conduction block (NCB). Pathologic features of CMTs typically include inflammation, hypertrophic changes, reduced axon diameters and (distal) axon loss. The resulting neurological disability can range from minor to severe. How SC defects drive this array of cellular pathologies and what mechanisms underlie the clinical spectrum of CMTs are key questions with important translational implications. To interrogate how SC pathology impacts axon biology and leads to clinical defects, we are characterizing mice in which two key SC proteins, Egr2 and the G coupled protein receptor, Gpr126 have been deleted. Conditional knockouts (cKOs) of either of these proteins arrest SCs at the promyelinating stage and blocks their ability to form myelin. Yet these mice have very different phenotypes: Gpr126 cKOs are mildly affected and have a normal life span whereas Egr2 cKOs are progressively paralyzed and moribund by 3-4 months of age. As expected, NCV is markedly slow in both mutants. However, only the Egr2 cKOs exhibit frank NCB, a likely driver of their severe disability. Correspondingly, these mutants have very distinct nerve pathologies. Egr2 cKOs nerves are markedly inflamed, hypertrophic, and their axons are significantly smaller as compared to Gpr126 cKOs. To further elucidate differences between these mutants, we will investigate: i) the role of inflammation in their respective phenotypes and why these dysmyelinating SCs differentially activate inflammation, ii) examine the mechanisms by which these SC mutations regulate axon diameter and iii) use single nuclei RNAseq to characterize changes in the transcriptomes of SCs that impact axon biology and function in nerve conduction. These studies should provide important new insights into how SC pathology impacts axon biology and function and may lead to new therapeutic strategies to ameliorate disability in disorders of myelinated fibers.

轴突和雪旺细胞 (SC) 之间的相互作用驱动轴突的形成、功能和维护有髓神经，这对于有效的跳跃传导和神经功能至关重要。外在来自轴突和基底层 (BL) 的信号协同驱动一系列 SC 转录的表达因子 (TF)，最终导致 Egr2 的表达，Egr2 是三七总皂苷 (PNS) 髓鞘形成的主要调节因子。需要 Egr2 SCs从早髓鞘阶段（当它们包裹轴突一次）前进到髓鞘形成阶段（当它们上调髓磷脂成分并形成多层髓鞘。髓鞘 SC 反过来重新组织轴突进入不同的域，特别是朗飞结，并增加轴突尺寸。这些集体的改变通过跳跃传导实现并优化动作电位传播。此项规定的重要性 SC 的轴突生物学强调了与获得性和遗传性相关的残疾（例如，Charcot Marie 髓鞘 SC (mSC) 的牙齿 (CMT) 疾病。由各种 SC 突变引起的 CMT 会导致以神经传导速度 (NCV) 缓慢为特征的脱/髓鞘脱失，通常伴有神经传导阻滞（NCB）。 CMT 的病理特征通常包括炎症、肥大性改变、轴突减少直径和（远端）轴突损失。由此产生的神经功能障碍的范围可以从轻微到严重。如何SC 缺陷驱动了一系列细胞病理学，以及 CMT 临床谱的潜在机制是什么具有重要转化意义的关键问题。探究 SC 病理学如何影响轴突生物学并导致临床缺陷，我们正在表征小鼠，其中两种关键的 SC 蛋白 Egr2 和 G 偶联蛋白质受体 Gpr126 已被删除。这些蛋白质的条件敲除 (cKO) 会阻止 SC 在髓鞘形成阶段并阻止其形成髓磷脂的能力。然而这些小鼠具有非常不同的表型： Gpr126 cKO 受到轻微影响并具有正常寿命，而 Egr2 cKO 则逐渐瘫痪 3-4个月龄时濒临死亡。正如预期的那样，NCV 在两种突变体中均明显缓慢。然而，只有 Egr2 cKO 表现出明显的 NCB，这可能是其严重残疾的驱动因素。相应地，这些突变体具有非常独特的神经病理学。 Egr2 cKOs 神经明显发炎、肥大，轴突与 Gpr126 cKO 相比明显更小。为了进一步阐明这些突变体之间的差异，我们将研究：i) 炎症在其各自表型中的作用以及为什么这些髓鞘形成障碍 SC 差异性激活炎症，ii) 检查这些 SC 突变调节轴突的机制直径和 iii) 使用单核 RNAseq 来表征影响 SC 转录组的变化轴突生物学和神经传导功能。这些研究应该为如何 SC 病理学影响轴突生物学和功能，并可能导致新的治疗策略来改善有髓纤维疾病的残疾。