The Role of Astroglial-NF-kB in SCI

描述（由申请人提供）：在脊髓损伤（SCI）的进展过程中，第一阶段的损伤涉及机械组织破坏，随后是继发性损伤阶段，这是由于血液供应受损和侵袭细胞和驻扎细胞（如淋巴细胞、巨噬细胞、小胶质细胞和星形胶质细胞）释放促炎介质。星形胶质细胞通过诱导反应性星形胶质增生对损伤做出反应，这是一种深刻的细胞激活，其功能意义仍然存在争议。一方面，反应性星形胶质细胞释放神经元存活和修复所必需的神经营养素，另一方面，它们负责产生对功能恢复有害的促炎分子（细胞因子、趋化因子、生长因子、NO等）。许多发生在反应性星形胶质细胞中的过程是由NF-KB调控的，NF-KB是炎症和继发性损伤的关键调节剂。本提案中概述的研究旨在利用我们实验室生成的转基因小鼠模型来研究星形胶质NF-KB在SCI中的作用，其中NF-KB在星形胶质细胞中被选择性地失活。基于广泛的行为学研究提供的证据表明，这些转基因小鼠在脊髓损伤后比野生型小鼠表现出更大的功能恢复，我们假设脊髓损伤后星形胶质细胞中NF-KB的激活启动了转录程序，导致“有害的”星形胶质细胞形成，最终增加损伤。这一假设将在一系列实验中得到验证，具体目的如下：1)确定星形胶质细胞NF-KB失活对sci诱导炎症的影响。2)确定星形胶质NF-KB失活对脊髓损伤后细胞死亡的影响。3)观察星形胶质细胞nf - kb抑制对损伤脊髓瘢痕形成的影响。4)确定药物抑制NF-KB活化对脊髓损伤的治疗是否有效。这些研究将有助于阐明神经损伤后星形细胞中NF-KB激活的分子机制，以及它们如何影响胶质细胞和神经元细胞的存活和恢复。这将有助于更好地理解脊髓损伤的病理生理学，并可能开发出新的治疗干预策略。

DESCRIPTION (provided by applicant): In the progression of spinal cord injury (SCI), the first phase of injury, which involves mechanical tissue destruction, is followed by a phase of secondary injury, due to an impairment of blood supply and release of pro-inflammatory mediators from both invading and resident cells, such as lymphocytes, macrophages, microglia and astrocytes. Astrocytes respond to injury with the induction of reactive astrogliosis, a profound cellular activation whose functional significance is still a matter of debate. If, on one hand, reactive astrocytes release neurotrophins essential for neuronal survival and repair, on the other, they are responsible for production of pro-inflammatory molecules (cytokines, chemokines, growth factors, NO etc) detrimental to functional recovery. Many of the processes occurring in reactive astrocytes are regulated by NF-KB, a key modulator of inflammation and secondary injury. The studies outlined in this proposal are designed to investigate the role of astroglial NF-KB in SCI taking advantage of a transgenic mouse model generated in our laboratory, where NF-KB is functionally inactivated selectively in astrocytes. Based on extensive behavioral studies providing evidence that these transgenic mice display much greater functional recovery than wild type mice after SCI, we hypothesize that activation of NF-KB in astrocytes following SCI initiates transcriptional programs resulting in "deleterious" astrogliosis and ultimately increased damage. This hypothesis will be tested in a series of experiments organized in the following specific aims: 1) Determine the effect of inactivation of astroglial NF-KB on SCI-induced inflammation. 2) Determine the effect of inactivation of astroglial NF-KB on cell death following SCI. 3) Determine the effect of inhibition of astroglial-NF-KB on scar formation in the injured spinal cord. 4) Determine whether pharmacological inhibition of NF-KB activation is therapeutically effective in the treatment of SCI. These studies will contribute to the elucidation of the molecular mechanisms activated by NF-KB in astrocytes following SCI and how they can affect the survival and recovery of both glial and neuronal cells. This will lead to a better understanding of the pathophysiology of SCI and possibly to the development of novel strategies for therapeutic intervention.