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

• 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
• 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

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 在成人多发性硬化症(MS)等中枢神经系统疾病中白质束(WMI)受损后， 新生儿脑损伤导致脑瘫(CP)，髓鞘可通过激活再生 少突胶质前体细胞(OPC)。这种髓鞘再生计划的失败经常是由于不适当的 将OPC招募到损伤部位，大大促进了持续的神经功能障碍和疾病 进步。了解在髓鞘再生过程中控制OPC生物学的机制将提供深入的见解 为什么髓鞘修复在人类病例中失败。重要的是，OPC动态地产生初级纤毛，微管- 在一个专门的信号室中传递细胞间信号的细胞器。初级教师的角色 纤毛在调节OPC的发育途径中的作用仍然知之甚少。在这里，我们向您展示OPC 要求初级纤毛对WMI做出正确反应。首先，这笔赠款将证明从基因上移除 OPC的初级纤毛导致WMI修复不充分，确定初级纤毛是关键 WMI反应所必需的OPC中生物学变化的效应因子。此外，由于几乎没有 从机制上理解OPC中的纤毛信号通路，我们将使用以下方法的组合 最终确定从初级纤毛开始的GPCR/cAMP/CREB信号轴是一个重要的调节因子 OPC生物学的。最后，随着邻近标记技术的最新进展，我们现在可以对 使用一种名为纤毛-APEX的技术测量OPC主纤毛。这笔赠款将利用Cilia-APEX来识别 在体外和体内重新髓鞘形成过程中定位于OPC初级纤毛的信号分子。这将是 显示OPC初级纤毛在不同发育阶段蛋白质含量的动态变化 重新髓鞘形成，同时也增加了对OPC纤毛功能范围的显著洞察。加在一起，这些 研究表明，初级纤毛是OPC中调节重新髓鞘形成的关键信号模块， 并将揭示MS和CP等疾病的潜在治疗靶点，在这些情况下，OPC对损伤的反应 可能会出现功能障碍。 1