Periodic Reporting for period 1 - ChronicPain (New Target and Drug Candidates for Alleviating Chronic Pain)
Berichtszeitraum: 2019-11-01 bis 2021-04-30
Something like a quarter of the world’s population suffers from chronic and debilitating pain at some point in their lives. This project suggests an original approach to treating this affliction, by targeting a key gateway leading to the activation of genes in the peripheral nerve cells that play a role in many forms of chronic pain.
Pain starts in the sensory neurons -- those that pass information from the skin to the central nervous system. Damage to these neurons, chronic injury or disease can cause the neurons to “short circuit,” sending continuous pain messages. We investigated proteins called importins that regulate the biomolecular messaging activities taking place within these nerve cells. Behavioral screens on mutant mice implicated a particular importin -- importin alpha-3 -- in controlling pain pathways. Analyses of differences in the expression patterns between normal neurons and neurons lacking importin alpha-3 directed tour attention to c-Fos, a protein that importin alpha-3 brings into the nucleus. c-Fos is a transcription factor – a molecule that raises or lowers the expression of numerous genes. Further experiments in mice showed that c-Fos accumulates in the nucleus in peripheral nerve cells of mice suffering from chronic pain. Reduction or perturbation of importin alpha-3 or c-Fos in mouse peripheral nerve cells reduced responses to chronic pain. Screening of a specialized database which reveals connections between drugs and gene expression patterns then enabled the identification of around 30 existing drugs that might target the importin alpha-3—c-Fos pathway. Indeed, selected candidates from these compounds provided relief of neuropathic pain symptoms in mice.
Overall, the project has validated importin alpha-3 as a well-suited target for preventing or treating chronic pain, and has established assays and drug leads for this pathway.
Pain starts in the sensory neurons -- those that pass information from the skin to the central nervous system. Damage to these neurons, chronic injury or disease can cause the neurons to “short circuit,” sending continuous pain messages. We investigated proteins called importins that regulate the biomolecular messaging activities taking place within these nerve cells. Behavioral screens on mutant mice implicated a particular importin -- importin alpha-3 -- in controlling pain pathways. Analyses of differences in the expression patterns between normal neurons and neurons lacking importin alpha-3 directed tour attention to c-Fos, a protein that importin alpha-3 brings into the nucleus. c-Fos is a transcription factor – a molecule that raises or lowers the expression of numerous genes. Further experiments in mice showed that c-Fos accumulates in the nucleus in peripheral nerve cells of mice suffering from chronic pain. Reduction or perturbation of importin alpha-3 or c-Fos in mouse peripheral nerve cells reduced responses to chronic pain. Screening of a specialized database which reveals connections between drugs and gene expression patterns then enabled the identification of around 30 existing drugs that might target the importin alpha-3—c-Fos pathway. Indeed, selected candidates from these compounds provided relief of neuropathic pain symptoms in mice.
Overall, the project has validated importin alpha-3 as a well-suited target for preventing or treating chronic pain, and has established assays and drug leads for this pathway.