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.
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