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

项目摘要成人多发性硬化症 (MS) 等中枢神经系统疾病导致白质束 (WMI) 受损后新生儿脑损伤导致脑瘫（CP），髓鞘可以通过激活来再生少突胶质细胞前体细胞（OPC）。这种髓鞘再生计划的失败常常是由于不当的操作而发生的。 OPCs 募集到损伤部位，对持续的神经功能障碍和疾病有显着影响进展。了解髓鞘再生过程中控制 OPC 生物学的机制将提供见解为什么人类病例中髓磷脂修复失败。重要的是，OPC 动态产生初级纤毛、微管- 基于细胞器，在专门的信号室中转导细胞间信号。初级的作用纤毛在调节 OPC 发育途径中的作用仍知之甚少。在这里，我们展示了 OPC 需要初级纤毛对 WMI 做出正确反应。首先，这笔赠款将证明基因去除 OPC 的初级纤毛导致 WMI 修复不足，将初级纤毛确定为关键 WMI 反应所必需的 OPC 生物变化的效应器。此外，由于所剩无几为了对 OPC 中纤毛信号通路的机制有所了解，我们将使用以下方法的组合：最终定义了从初级纤毛开始的 GPCR/cAMP/CREB 信号轴作为关键的调节因子 OPC 生物学。最后，随着邻近标记的最新进展，我们现在可以对以下蛋白质进行编目：使用称为纤毛-APEX 的技术调查 OPC 初级纤毛。这笔赠款将利用 cilia-APEX 来识别体外和体内髓鞘再生过程中定位于 OPC 初级纤毛的信号分子。这将证明 OPC 初级纤毛蛋白质含量在不同阶段的动态变化髓鞘再生，同时还可以深入了解 OPC 中纤毛功能的程度。在一起，这些研究表明，初级纤毛是 OPC 中调节髓鞘再生的关键信号模块，并将揭示 MS 和 CP 等疾病的潜在治疗靶点，其中 OPC 对损伤的反应可能会出现功能障碍。 1