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Single cell transcriptomics of nerves that lack Remak bundles

缺乏 Remak 束的神经的单细胞转录组学

基本信息

批准号：
10649087
负责人：
Lawrence S Kirschner
金额：
$ 7.88万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649087
关键词：
Ablation Abnormal Cell Address Adopted Affect Alleles Animals Applications Grants Atrial myxoma with lentigines Axon Benign Biological Models Biology C Fiber Cell Communication Cell Proliferation Cell physiology Cells Charcot-Marie-Tooth Disease Cyclic AMP-Dependent Protein Kinases Data Defect Development Disease Embryonic Development Environment Esthesia Exhibits Family Fiber Functional disorder Future Human Individual Inherited Knowledge Laboratories Location Mediating Modeling Molecular Monomeric GTP-Binding Proteins Morphology Motor Mus Myelin Myelin Sheath NF1 gene Nerve Neural Conduction Neural Crest Cell Neurilemmoma Neurofibromatoses Neurofibromin 2 Neurons Nociception Outcome Pain Pathway interactions Patients Peripheral Peripheral Nervous System Peripheral Nervous System Malignant Neoplasms Phenotype Physiological Pilot Projects Play Population Process Proliferating Proprioception Proteins Role Schwann Cells Sensory Signal Pathway Signal Transduction Signaling Molecule Structure Supporting Cell Symptoms Syndrome Touch sensation Transcript Work afferent nerve cell growth cell type improved in vivo mouse model mutant neoplastic cell nerve damage pain perception protein activation response rho single cell analysis single-cell RNA sequencing transcriptome transcriptomics transmission process tumor tumorigenesis

项目摘要

PROJECT ABSTRACT Schwann cells (SCs) are neural crest derived cells whose primary function is the support and protection of neurons in the peripheral nervous system. SCs can be divided into two subtypes: myelinating and non- myelinating. Myelinating SCs form 1:1 relationships with neurons and ensheath them in myelin to provide rapid conduction of nerve impulses, such as those required for transduction of proprioception and touch. In contrast, non-myelinating SCs typically bundle multiple axons into nerve structures known as Remak bundles, which support the cells but do not speed transmissions. Individuals with dysfunction of SCs exhibit a variety of phenotypes which may include decreased sensation, weakness, and pain, and these diseases are among the most common inherited conditions in humans. In addition, SCs are also the cell type targeted for tumorigenesis in the Neurofibromatosis syndromes (NF1 and NF2) which ae associated with benign and malignant tumors of the peripheral nerves and other locations. Rac1 is a small GTPase protein of the Rho family, and it has been shown to essential for tumorigenesis in both NF1- and NF2-associated tumors, as well as other forms of inherited Schwann cell tumors (e.g., Carney Complex). Recently, analyses of inherited SC dysfunctional syndromes have also shown dysregulation of Rac1. To investigate the role of Rac1 signaling in SC function and tumorigenesis, my laboratory has generated a mouse model carrying a conditionally active allele of Rac1 and performed preliminary characterization of the effects of activation Rac1 at various stages of SC development. We observe that activation of Rac1 in early embryogenesis enhanced cell proliferation and affects the ability of non- myelinating SCs to form normal Remak bundles, which are completely absent from nerves with Rac1 activated in early embryogenesis. In this R03 application, we hypothesize that Rac1 activation leads to aberrant differentiation specifically in non-myelinating SCs without affecting the trajectory of myelinating SCs. Initial characterization of this defect through this pilot grant application will lead to future studies with important implications for nociception and for tumorigenesis. To address this hypothesis, we propose the single Specific Aim to assess the differential effects of activation of Rac1 on the transcriptomes of myelinating and non-myelinating Schwann cells. As a first step, will compare the transcriptomes of WT SCs to the abnormal SCs in mice with SC-targeted early activation of Rac1. Secondly, we will expand the analysis to include mice with later activation of Rac1, as these animals appear to have morphologically and functional normal SCs. Thirdly, we will validate these data by analyzing specific transcripts and proteins to verify the transcriptomic changes. If successful, these studies will begin to elucidate the important molecular functions of Rac1 in mediating the differentiation, physiologic function, and tumor implications of Schwann cells in vivo, with implications both for understanding and treating pain, and for understanding SC tumorigenesis such as in NF.

项目摘要