ROLE OF SW1/SNF FACTORS IN SCHWANNOMATOSIS ASSOCIATED PAIN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 顽固性疼痛是神经鞘瘤病的常见特征。 神经鞘瘤病患者所经历的疼痛与神经鞘瘤的质量或这些肿瘤对神经的压迫没有严格的联系，这表明神经鞘瘤病相关的疼痛可能是由其他方式引起的。 神经鞘瘤病与Snf 5（INI 1/SMARCB 1）基因突变有关。 Snf 5是SWI/SNF染色质重塑因子的亚基，其ATP酶亚基Brg 1或Brm通过重塑染色质的选定区域来影响基因激活或抑制。 我们发现，小鼠与巢蛋白靶向损失的Brg 1表现出参与神经性疼痛的神经营养因子的水平升高，并表现出交感神经发芽到感觉神经节-一个过程，建议影响神经性疼痛，这可能是由雪旺细胞衍生的细胞因子或生长因子。 我们的假设是SWI/SNF因子，特别是Snf 5作为编码某些神经营养因子或其他疼痛介质的基因的共阻遏物。我们进一步假设Snf 5突变的雪旺细胞释放这些因子并诱导疼痛。我们将通过（1）确定Snf 5的缺失是否导致相同因子的上调，在Brg 1缺失的感觉神经元和雪旺细胞中表达增加;（2）进行筛选，比较野生型和Snf 5突变的小鼠雪旺细胞中神经营养因子的表达，集中于已知的神经性疼痛介质，以确定Snf 5-SWI/SNF蛋白复合物是否抑制这些介质;和（3）测试雪旺细胞中Snf 5的条件性缺失是否影响感觉神经元和雪旺细胞中Snf 5缺失的小鼠中的伤害感受反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Intractable pain is a common feature of schwannomatosis. The pain experienced by schwannomatosis patients is not strictly linked to the mass of schwannomas or to nerve compression by these tumors, suggesting that schwannomatosis-associated pain may be induced by other means. Schwannomatosis is linked to mutations in the Snf5 (INI1/SMARCB1) gene. Snf5 is a subunit of SWI/SNF chromatin remodeling factors whose ATPase subunits, Brg1 or Brm, influence gene activation or repression by remodeling selected areas of chromatin. We found that mice with nestin-targeted loss of Brg1 demonstrate elevated levels of neurotrophic factors implicated in neuropathic pain and demonstrate sympathetic sprouting into sensory ganglia - a process suggested to influence neuropathic pain and which may be regulated by Schwann cell-derived cytokines or growth factors. Our hypothesis is that SWI/SNF factors and, in particular, Snf5 act as co-repressors of genes encoding certain neurotrophic factors or other pain mediators. We further postulate that Snf5-mutant Schwann cells release these factors and induce pain. We will test this hypothesis by (1) determining if loss of Snf5 results in the upregulation of the same factors with increased expression in Brg1-null sensory neurons and Schwann cells; (2) performing screens comparing neurotrophin expression in wild type and Snf5-mutant mouse Schwann cells, focusing on known mediators of neuropathic pain, to determine if Snf5-SWI/SNF protein complexes repress these mediators; and (3) testing if the conditional loss of Snf5 in Schwann cells influences nociceptive responses in sensory neurons and in mice with loss of Snf5 in their Schwann cells.