The Role of Astroglial-NF-kB in SCI

描述（由申请人提供）：在脊髓损伤（SCI）的进展中，损伤的第一阶段涉及机械组织破坏，随后是继发性损伤的阶段，这是由于血液供应受损以及来自侵入细胞和驻留细胞（如淋巴细胞、巨噬细胞、小胶质细胞和星形胶质细胞）的促炎介质的释放。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活化，其功能意义仍有争议。如果，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因子，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）。反应性星形胶质细胞中发生的许多过程受NF-κ B调节，NF-κ B是炎症和继发性损伤的关键调节剂。 在这个建议中概述的研究旨在研究星形胶质细胞NF-κ B在SCI中的作用，利用我们实验室产生的转基因小鼠模型，其中NF-κ B在星形胶质细胞中选择性地功能失活。 基于广泛的行为研究提供的证据表明，这些转基因小鼠显示更大的功能恢复比野生型小鼠后SCI，我们假设，激活NF-κ B的星形胶质细胞后SCI启动转录程序，导致“有害的”星形胶质细胞增生，并最终增加损害。该假设将在以下具体目的组织的一系列实验中进行测试：1）确定星形胶质细胞NF-κ B的失活对SCI诱导的炎症的影响。2)确定星形胶质细胞NF-κ B失活对SCI后细胞死亡的影响。3)确定抑制星形胶质细胞-NF-κ B对损伤脊髓中瘢痕形成的影响。4)确定NF-κ B活化的药理学抑制在SCI治疗中是否有效。这些研究将有助于阐明SCI后星形胶质细胞中NF-κ B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。这将导致更好地理解SCI的病理生理学，并可能发展新的治疗干预策略。

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.