The Role of Histone Acetylation in Potassium-Chloride Co-Transporter 2 Expression Following the Complete Freund's Adjuvant (CFA)-Induced Inflammation

Multiple mechanisms contribute to the stimulus-evoked pain hypersensitivity that may be experienced after peripheral inflammation in response to normally innocuous and noxious stimuli. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications. Histones are proteins in close contact with the DNA in the nucleus of a cell. They function to maintain the organization of DNA, and recent studies have shown that histones regulate the expression of genes. Histones can be modified by biochemical processes such as addition or removal of acetyl groups, known as acetylation and deacetylation. Such modifications have been shown to control genetic mechanisms important for central sensitization. The aim of our study is to examine the role for epigenetic modification of Slc12a5 (encoding Potassium-chloride co-transporter 2 (KCC2)) in the persistence of inflammatory pain. The goal of this project is to tease the contribution of histone acetylation of KCC2 gene. The following specific hypotheses will be examined: 1) persistent inflammatory pain decreases GABAergic synaptic function. 2) Persistent pain epigenetically reduces KCC2 expression. 3) Histone hyperacetylation increases GABA synaptic function. 4) Histone hyperacetylation relieved pain. 5) Histone-hyperacetylation-induced pain relief requires KCC2. There are multiple causes of inflammatory pain, but in spite of recent advances, this condition remains poorly controlled and is a major public health problem. Our ultimate goal is the identification of the role of histone acetylation responsible for KCC2 expression regulation since this may offer new treatment strategies for inflammatory pain aimed at preventing or reversing hyperalgesia.

Project ID:PC10207-0829
External Project ID:NSC102-2314-B182-029