The Role of Astroglial-NF-kB in SCI

描述(申请人提供)：在脊髓损伤(SCI)的发展过程中，第一阶段的损伤涉及机械组织破坏，紧随其后的是第二阶段的损伤，这是由于侵袭性细胞和常驻细胞(如淋巴细胞、巨噬细胞、小胶质细胞和星形胶质细胞)的血液供应和促炎介质的释放受损。星形胶质细胞对损伤的反应是诱导反应性星形胶质细胞增生，这是一种深刻的细胞激活，其功能意义仍然存在争议。如果反应性星形胶质细胞一方面释放对神经元生存和修复至关重要的神经营养因子，另一方面，它们负责产生不利于功能恢复的促炎分子(细胞因子、趋化因子、生长因子等)。发生在反应性星形胶质细胞中的许多过程都受到核因子-kB的调控，核因子-kB是炎症和继发性损伤的关键调节器。这项建议中概述的研究旨在利用我们实验室建立的转基因小鼠模型来研究星形胶质细胞核因子-kB在脊髓损伤中的作用，在该模型中，星形胶质细胞中的核因子-kB在功能上是选择性失活的。基于广泛的行为学研究表明，这些转基因小鼠在脊髓损伤后表现出比野生型小鼠更大的功能恢复，我们假设脊髓损伤后星形胶质细胞中核因子-KB的激活启动了转录程序，导致了有害的星形胶质细胞增生，并最终增加了损伤。这一假说将在以下特定目的的一系列实验中得到验证：1)确定星形胶质细胞核因子-KB失活在脊髓损伤诱导的炎症反应中的作用。2)研究星形胶质细胞核因子-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-核因子-KB对脊髓损伤后瘢痕形成的抑制作用。4)确定药物抑制核因子-kB活化在治疗脊髓损伤中是否有效。这些研究将有助于阐明脊髓损伤后星形胶质细胞中核因子-KB激活的分子机制，以及它们如何影响神经胶质细胞和神经细胞的存活和恢复。这将导致更好地理解脊髓损伤的病理生理学，并可能开发新的治疗干预策略。

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.