Spatial Regulators of Skeletal Muscle Regeneration and Disease

骨骼肌再生和疾病的空间调节器

• 批准号: 10619138
• 负责人: YU XIN WANG
• 金额: $ 24.87万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619138
• 关键词: Acute; Algorithms; Antibodies; Autoimmune; Autoimmune Responses; Autoimmunity; Behavior; Bioinformatics; Biological Process; Biology; Breathing; Cell Communication; Cells; Chronic; Collaborations; Computational algorithm; Cytometry; Data; Denervation; Development; Disease; Experimental Autoimmune Myasthenia Gravis; Goals; Healthcare; Image; Imaging technology; Immune; Injury; Ligands; Macrophage; Maps; Mentors; Metabolism; Methods; Modeling; Molecular; Motor Neurons; Movement; Muscle; Muscle Cells; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Atrophy; Myasthenia Gravis; Myopathy; Natural regeneration; Nerve; Nerve Crush; Neuroglia; Neuromuscular Diseases; Neuromuscular Junction; PTPRC gene; Persons; Phase; Population; Posture; Process; Quality of life; Research; Resolution; Role; Signal Transduction; Signaling Molecule; Skeletal Muscle; Sprains and Strains; Standardization; Technology; Tissues; Training; Visualization; age related; care burden; cell type; connectome; effective therapy; empowerment; experimental study; high dimensionality; in vitro regeneration; in vivo; insight; intercellular communication; mdx mouse; mouse model; multiplexed imaging; muscle regeneration; myogenesis; nerve injury; neuromuscular; new technology; novel; progenitor; programs; reinnervation; repaired; response; restoration; sarcopenia; sciatic nerve; stem cell function; stem cells; strain injury; success; therapy development; tissue regeneration; tissue repair; transcriptomics; unsupervised learning

Skeletal muscles are responsible for movement, breathing, posture and metabolism. Loss of muscle function via acute injury or chronic neuromuscular disease (NMD) is debilitating to quality of life and is associated with high healthcare burden. In the US, there are over 12 million cases of sprains and strains injuries each year, an estimated 50 million people living with age-related sarcopenia, and another 250,000 with NMDs. My long-term goal is to elucidate the cellular and molecular mechanisms which underlie the muscle repair and develop therapies for chronic muscle disorders. A major barrier in this endeavor is our limited of understanding of the multiplicity of cell types involved during muscle regeneration. Little is known regarding functions of each cell type and how they interact with tissue-resident stem cells to regulate the restoration of muscle function. Thus, tissue cytometry, the mapping of single cells within tissues, is necessary to gain novel insights into cellular interactions during muscle regeneration and in dysregulated disease states. My central hypothesis is that local signaling in the cellular microenvironment regulate the behavior of critical cell types to remodel or repair the tissue. To this, I have optimized a novel multiplexed imaging technology (CODEX) that enables visualizes 40+ antibodies on a single muscle section. In the proposed research, I aim to (i) develop technologies to study cellular interactions using high dimensional imaging data and build a single cell resolution spatial map of the localization, abundance, dynamics, and interactions of 25 cell type within normal muscle regeneration and disease states; (ii) elucidate critical cell types and spatially-localized signaling that determine the proper expansion and differentiation of muscle stem cells; (iii) deep profile the function of M2 macrophages and fibroadipogenic precursors in process of motor neuron and neuromuscular junction remodeling. The training I will receive during the mentored phase of this proposal will be critical for the success of this project. Moreover, application of this systematic approach to study inter-cellular signaling will allow me to achieve academic independence. The proposed experiments in the K99 phase will provide novel insights into the coordinated process of tissue regeneration and will yield candidate signaling molecules with the potential to modulate the function of muscle stem cells. Further, the proposed project for the R00 phase will lead to better understanding of the cellular responses and fundamental mechanisms of motor neuron and neuromuscular junction remodeling, which has significant relevance for nerve injuries and chronic autoimmune neuromuscular diseases.

骨骼肌肉负责运动，呼吸，姿势和代谢。通过急性损伤或慢性神经肌肉疾病（NMD）失去肌肉功能的丧失使生活质量衰弱，并且与高医疗保健负担有关。在美国，每年有超过1200万例扭伤和菌株受伤，估计有5000万人患有与年龄有关的肌肉减少症，另有25万例NMD。我的长期目标是阐明肌肉修复和发展慢性肌肉疾病疗法的细胞和分子机制。这项工作的主要障碍是我们对肌肉再生过程中所涉及的多种细胞类型的了解有限。关于每种细胞类型的功能以及它们如何与组织居住的干细胞相互作用以调节肌肉功能的恢复，知之甚少。因此，组织细胞术，组织中单细胞的映射，对于在肌肉再生期间和失调的疾病状态下，需要对细胞相互作用进行新的见解。我的中心假设是，细胞微环境中的局部信号传导调节关键细胞类型重塑或修复组织的行为。为此，我优化了一种新型的多重成像技术（Codex），该技术可以在一个肌肉部分上可视化40多个抗体。在拟议的研究中，我的目标是（i）开发技术，使用高维成像数据研究细胞相互作用，并在正常肌肉再生和疾病状态中建立25种细胞类型的定位，丰度，动力学和相互作用的单个细胞分辨率空间图； （ii）阐明关键细胞类型和空间定位的信号传导，以确定肌肉干细胞的适当扩展和分化； （iii）深层剖面在运动神经元和神经肌肉连接重塑过程中M2巨噬细胞和纤维型前体的功能。我将在该提案的指导阶段接受的培训对于该项目的成功至关重要。此外，这种系统的方法在研究细胞间信号传导中的应用将使我能够实现学术独立性。在K99阶段提出的实验将提供对组织再生过程协调过程的新见解，并产生候选信号分子，并具有调节肌肉干细胞功能的潜力。此外，R00阶段的拟议项目将更好地理解运动神经元和神经肌肉连接重塑的细胞反应和基本机制，这与神经损伤和慢性自身免疫神经肌肉疾病具有重要意义。