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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（SCs）之间的相互作用驱动了其形成、功能和维持