Mechanisms of oligodendroglial ciliary function in white matter injury repair

少突胶质细胞纤毛功能在白质损伤修复中的机制

基本信息

批准号：
10659990
负责人：
Stephen Philip James Fancy
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2023-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659990
关键词：
Acute Adult Affect Agonist Area Biological Blood Vessels CREB1 gene Catalogs Cell Communication Cell Culture Techniques Cell Proliferation Cells Cellular biology Central Nervous System Diseases Cerebral Palsy Cilia Collaborations Cues Cyclic AMP Data Demyelinations Development Disease Disease Progression Enzymes Erinaceidae Failure G-Protein-Coupled Receptors Gene Expression Gene Targeting Genes Grant Homeostasis Human Image In Vitro Injury Label Lesion Letters LoxP-flanked allele Mammalian Cell Maps Mediating Methods Microtubules Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelin Sheath Natural regeneration Nature Neurologic Dysfunctions Organelles Pathway interactions Pericytes Population Proliferating Proteins Proteome Regulation Rest Role Signal Pathway Signal Transduction Signaling Molecule Site Slice Spinal Cord Surveys Techniques Tissues Transducers Transgenic Organisms Visualization cell behavior cell type hypoxia neonatorum in vivo injury and repair insight mRNA sequencing migration neonatal human nervous system disorder newborn brain injury oligodendrocyte precursor oligodendrocyte progenitor pharmacologic precursor cell progenitor programs recruit remyelination repaired response response to injury stem cells therapeutic target tool white matter white matter injury

项目摘要

PROJECT ABSTRACT After damage to white matter tracts (WMI) in CNS diseases such as multiple sclerosis (MS) in adults and newborn brain injuries that cause cerebral palsy (CP), myelin sheaths can be regenerated by activated oligodendrocyte precursor cells (OPCs). Failure of this remyelination program often occurs due to the improper recruitment of OPCs into injury sites, contributing significantly to ongoing neurological dysfunction and disease progression. Understanding the mechanisms controlling OPC biology during remyelination will provide insights as to why myelin repair fails in human cases. Importantly, OPCs dynamically produce primary cilia, microtubule- based organelles that transduce intercellular cues in a specialized signaling compartment. The role of primary cilia in regulating developmental pathways in OPCs remains poorly understood. Here, we show that OPCs require primary cilia to respond properly to WMI. First, this grant will demonstrate that genetically removing primary cilia from OPCs results in inadequate WMI repair, identifying the primary cilium as a critical effector of biological change in OPCs necessary for the WMI response. Furthermore, as there remains little mechanistic understanding of ciliary signaling pathways in OPCs, we will use a combination of approaches that ultimately define a GPCR/cAMP/CREB signaling axis beginning at the primary cilium as a crucial regulator of OPC biology. Finally, with recent advances in proximity-labeling, we can now catalogue the proteins that survey OPC primary cilia using a technique termed cilia-APEX. This grant will utilize cilia-APEX to identify signaling molecules that localize to OPC primary cilia in vitro and during remyelination in vivo. This will demonstrate dynamic changes in the protein content of OPC primary cilia during different stages of remyelination, while also adding significant insight into the extent of ciliary functions in OPCs. Together, these studies will show that primary cilia are a critical signaling module in OPCs for the regulation of remyelination, and will reveal potential therapeutic target for conditions such as MS and CP, where the OPC response to injury can be dysfunctional. 1

项目摘要在中枢神经系统疾病中损坏了白质区（WMI）之后，例如成人多发性硬化症（MS）和引起脑瘫（CP）的新生儿脑损伤，髓鞘可以通过激活而再生少突胶质细胞前体细胞（OPC）。此延期计划的失败通常是由于不当而发生的将OPC招募到损伤部位，极大地导致了持续的神经功能障碍和疾病进展。了解控制OPC生物学期间的机制将提供见解至于为什么在人类病例中修复髓磷脂的原因。重要的是，OPC动态产生原代纤毛，微管在专门的信号隔间中传递细胞间提示的基于细胞器。主要角色纤毛在调节OPC中的发育途径方面仍然知之甚少。在这里，我们证明了OPC 要求初级纤毛对WMI正确响应。首先，这笔赠款将证明遗传上的去除 OPC的原发性纤毛导致WMI修复不足，从而将主要纤毛识别为关键 WMI响应所需的OPC生物变化的效应因子。此外，由于几乎没有对OPC中睫状信号通路的机械理解，我们将使用多种方法的组合最终定义GPCR/CAMP/CREB信号轴，从主要纤毛开始作为关键调节器 OPC生物学。最后，随着接近标记的最新进展，我们现在可以分类的蛋白质分类使用称为Cilia-Apex的技术调查OPC主要纤毛。该赠款将利用纤毛 - apex来识别信号分子在体外及其在体内再生期间定位于OPC原发性纤毛。这会在不同阶段的OPC主要纤毛蛋白质含量的动态变化透明度，同时还增加了对OPC中睫状功能程度的重要见解。在一起，这些研究将表明，原发性纤毛是OPC中的关键信号传导模块，用于调节再生，并将揭示对MS和CP等疾病的潜在治疗靶标的，其中OPC对损伤的反应可能是功能失调的。 1