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，随后是一个有效的再生反应，重建组织结构和功能。然而，在哺乳动物中枢神经系统（CNS）中，损伤通常导致永久性改变组织功能的持续性病变，有时甚至导致进行性神经功能缺损。尽管中枢神经系统对损伤的耐受性差且再生能力低，但对急性中枢神经系统损伤的反应可能是可变的，从不可逆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。这一领域进展的主要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，随后都是包含不同细胞类型（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，以及浸润性免疫细胞）的多细胞反应。因此，本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特性，并确定控制组织损伤延续和功能恢复之间平衡的检查点。我们探索由炎症、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是否经历再生或瘢痕反应的潜在机制。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生命内、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。我们的目标是确定确定中枢神经系统损伤结果的免疫、神经胶质和神经元检查点，并制定针对这些检查点的干预策略，指导受伤的中枢神经系统组织重建。在第一个资助期，我们的重点是分析不同的损伤模型、细胞反应、亚细胞改变和决定恢复的分子信号。在第二个资助期，我们希望以这些见解为基础，并强调以下方法：1)剖析损伤后免疫、神经胶质和神经元反应之间的细胞网络和相互作用；2)整合不同损伤模型的发现，以揭示恢复过程的共享和疾病特异性原则；3)验证人体组织样本和人源化模型系统中的实验发现。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修复和限制疤痕。

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.