Building a Molecular Atlas of Macrophage Contributions to Successful Spinal Cord Regeneration

建立巨噬细胞对脊髓成功再生贡献的分子图谱

• 批准号: 10181595
• 负责人: Claire Williams
• 金额: $ 5.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-05-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10181595
• 关键词: Acute; Adolescent; Adult; Ambystoma; Amputation; Anti-Inflammatory Agents; Apoptosis; Architecture; Atlases; Bioinformatics; Biological Assay; Cell Differentiation process; Cell Proliferation; Cells; Cicatrix; Clinical; Communication; Communities; Competence; Cytokine Gene; Cytokine Signaling; Data; Databases; Development; Event; Exhibits; Fellowship; Future; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Goals; Human; Immune; Immune response; Immune system; Immunologic Factors; Impairment; Individual; Inflammation; Inflammatory; Injury; Investigation; Lead; Leadership; Ligands; Maps; Measures; Mentorship; Microglia; Modeling; Molecular; Monitor; Motor; Mus; Natural regeneration; Nerve Regeneration; Neuraxis; Neurons; Operative Surgical Procedures; Organism; Outcome; Play; Positioning Attribute; Rana; Recovery; Regenerative capacity; Research; Research Personnel; Role; Sensory; Site; Spatial Distribution; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Tadpoles; Tail; Technical Expertise; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; United States; Universities; Vertebrates; Washington; Work; Xenopus; Zebrafish; axon growth; career; cell injury; experience; fall injury; falls; genetic analysis; improved; innovation; insight; interest; macrophage; multidimensional data; nerve stem cell; neuroimmunology; neuroinflammation; neuronal survival; novel; novel therapeutics; programs; regenerative; response; single cell analysis; skills; spatiotemporal; spinal cord regeneration; success; targeted treatment; therapeutic candidate; therapeutic target; tissue regeneration; tool; transcriptomics; wound; wound healing

Spinal cord injury (SCI) induces a cascade of cellular events as severely damaged cells undergo apoptosis and assorted immune cells migrate to the injury. This immune response is critical to the long-term outcome, with inflammation playing an important role in secondary damage, wound repair and fibrotic scar formation. Despite recent advances, regenerative capacity in humans following SCI remains low. One valuable way to inspire new progress is to turn to other organisms which exhibit spontaneous recovery from SCI to explore the mechanisms that they use in regeneration. Among vertebrates able to regenerate, the frog Xenopus tropicalis is of particular interest because it shows developmentally-modulated regenerative capacity, able to regenerate its spinal cord in tadpole stages yet unable to regenerate in adult stages. As in other regenerative vertebrates, macrophages, including spinal cord resident microglia, are required for successful regeneration in young tadpoles, suggesting a conserved intimate association of the immune system with regeneration. In this proposal, I will spatially map the immune and neural cell states that follow SCI in efficient regeneration. From this multidimensional dataset, I will identify candidate beneficial immune factors and use genetic tools to test the necessity of these factors in successful spinal cord regeneration. Next, I will test the necessity of macrophages in juvenile spinal cord regeneration and comprehensively analyze changes in the macrophage response to SCI that coincide with a loss of regenerative capacity in frogs. Together, the generation of spatiotemporal atlases of successful regeneration, functional investigations into immune system modulation, and careful annotations of the incremental cell state alterations that accompany impaired regeneration, will provide a rich database from which to generate novel therapeutic candidates to promote neuronal survival and regeneration following SCI in humans. This fellowship will be completed under the mentorship of Dr. Cole Trapnell and Dr. Andrea Wills at the University of Washington, where I will have ample interactions with a vibrant community of researchers in the fields of neuroinflammation, regeneration, and transcriptomics. The primary training goals of this proposal are uniquely crafted to aid my career progression and will enhance my neuroimmunology background, expand my technical expertise, bolster my statistical training, improve my scientific communication skills, and increase my leadership experience. At the conclusion of this fellowship, I will have an established research program and will be well-positioned to advance into an independent position.

脊髓损伤（SCI）诱导一系列细胞事件，因为严重受损的细胞发生凋亡，各种免疫细胞迁移到损伤处。这种免疫反应对长期结果至关重要，炎症在继发性损伤、伤口修复和纤维化瘢痕形成中起着重要作用。尽管最近取得了进展，但SCI后人类的再生能力仍然很低。激发新进展的一个有价值的方法是转向其他从SCI中自发恢复的生物体，以探索它们在再生中使用的机制。在能够再生的脊椎动物中，热带爪蟾蛙特别令人感兴趣，因为它显示出发育调节的再生能力，能够在蝌蚪阶段再生脊髓，但在成年阶段不能再生。与其他再生脊椎动物一样，巨噬细胞，包括脊髓驻留的小胶质细胞，是年轻蝌蚪成功再生所必需的，这表明免疫系统与再生有着保守的密切联系。在这个提议中，我将在空间上映射SCI后有效再生的免疫和神经细胞状态。从这个多维数据集中，我将确定候选的有益免疫因子，并使用遗传工具来测试这些因子在成功的脊髓再生中的必要性。接下来，我将测试巨噬细胞在幼年脊髓再生中的必要性，并全面分析与青蛙再生能力丧失相一致的巨噬细胞对SCI反应的变化。总之，生成成功再生的时空图谱，对免疫系统调节的功能研究，以及伴随受损再生的增量细胞状态改变的仔细注释，将提供丰富的数据库，从中产生新的治疗候选物，以促进人类SCI后神经元的存活和再生。这项研究将在华盛顿大学的科尔·特拉普内尔博士和安德烈·威尔斯博士的指导下完成，在那里，我将与神经炎症、再生和转录组学领域充满活力的研究人员社区进行充分的互动。本提案的主要培训目标是为了帮助我的职业发展而精心设计的，并将增强我的神经免疫学背景，扩大我的技术专长，加强我的统计培训，提高我的科学沟通技能，并增加我的领导经验。在这个奖学金的结论，我将有一个既定的研究计划，并将很好地定位到一个独立的位置前进。