TRR 274: Checkpoints of Central Nervous System Recovery

在大多数器官中，组织损伤是一个可逆的过程，紧随其后的是重建组织结构和功能的有效再生反应。然而，在哺乳动物的中枢神经系统(CNS)中，损伤往往会导致永久性的组织功能改变，有时甚至会导致进行性的神经功能障碍。尽管中枢神经系统对损伤的耐受性差，再生能力低，但对急性中枢神经系统损伤的反应可能是多种多样的，从不可逆转的损伤到几乎完全恢复。造成这些不同结果的根本原因尚不清楚。在这一领域取得进展的一个中心障碍是中枢神经系统损伤反应的复杂生物学基础，无论其触发因素如何，紧随其后的是包括不同细胞类型(包括神经元、星形胶质细胞、小胶质细胞、少突胶质细胞及其前体细胞以及浸润性免疫细胞)的多细胞反应。因此，该CRC的主要目的是了解决定中枢神经系统损伤后恢复的多细胞反应的生物学，并确定控制组织损伤的永久性和功能恢复之间的平衡的检查点。我们探索炎症、创伤、代谢功能障碍或缺血引起的各种急性中枢神经系统损伤和重建的独特模式，并试图揭示决定组织经历再生反应或疤痕反应的潜在机制。我们的CRC由免疫学家、神经生物学家和神经胶质生物学家组成，专门从事急性中枢神经系统损伤的活体内、细胞生物学和分子分析。这些互补的专业知识和方法使我们能够揭示和调节细胞相互作用及其结构和功能后果，以及它们潜在的分子信号和途径。我们的目标是确定决定中枢神经系统损伤结果的免疫学、神经胶质和神经元检查点，并针对这些检查点制定干预策略，引导受损的中枢神经组织走向重建。在第一个资助期，我们的重点是分析不同的损伤模型和决定恢复的细胞反应、亚细胞变化和分子信号。在第二个资助期，我们希望在这些见解的基础上，强调以下方法：i)解剖细胞网络和相互作用，这些细胞网络和相互作用将损伤后的免疫、神经胶质和神经元反应联系在一起；ii)整合不同损伤模型的研究结果，以揭示共同的和疾病特有的恢复过程原理；iii)在人体组织样本和人性化模型系统中验证实验结果。总之，这些研究将为设计新的治疗策略奠定基础，利用中枢神经系统的内源性修复潜力来促进组织重建和限制疤痕形成。

In most organs, tissue damage is a reversible process that is followed by an efficient regenerative response that re-establishes tissue structure and function. In the mammalian central nervous system (CNS), however, injuries often result in persistent lesions that permanently alter tissue function and sometimes even result in progressive neurological deficits. Despite the CNS’ poor tolerance to damage and its low regenerative capacity, the response to acute CNS injury can be variable and ranges from irreversible damage to almost complete recovery. The underlying reasons for these different outcomes are unknown. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury which, irrespective of its trigger, is followed by a multicellular response that encompasses different cell types (including neurons, astrocytes, microglia, oligodendrocytes, and their precursors, as well as infiltrating immune cells). Therefore, the major aim of this CRC is to understand the biology of the multicellular response that determines recovery after CNS injury and to identify the checkpoints that govern the balance between perpetuation of tissue damage and restitution of function. We explore the unique patterns of damage and reconstitution resulting from various acute insults to the CNS caused by inflammation, trauma, metabolic dysfunction, or ischemia and seek to unravel the underlying mechanisms that dictate whether the tissue undergoes a regenerative or scarring response. Our CRC consists of immunologists, neurobiologists, and glial biologists, specialized in intra-vital, cell-biological, and molecular analyses of acute CNS damage. These complementary expertises and approaches allow us to reveal and modulate cellular interactions and their structural and functional consequences as well as their underlying molecular signals and pathways. Our goal is to define the immunological, glial, and neuronal checkpoints that determine the outcome of CNS injuries, and to develop intervention strategies targeting those checkpoints that guide an injured CNS tissue towards reconstitution. In the first funding period our focus has been on the analysis of distinct damage models and the cellular responses, subcellular alterations, and molecular signals that determine recovery. In the second funding period we want to build on these insights and emphasize approaches that allow i) dissecting the cellular networks and interactions that interconnect immune, glial and neuronal responses after injury, ii) integrating findings across distinct injury models to reveal shared and disease-specific principles of the recovery process and iii) validating experimental findings in human tissue samples and humanized model systems. Together, these studies will lay the foundation for the design of novel treatment strategies that harness the endogenous repair potential of the CNS to promote tissue restitution and limit scarring.