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.
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