Tuesday, May 7, 2024
5/7/2024
PROJECT SUMMARY Chronic neuropathic pain is a devastating condition that significantly impacts quality of life. Better understanding of how acute nerve injury transitions to chronic neuropathic pain is therefore a key initiative of pain research. Transition to neuropathic pain frequently involves central sensitization, where nociceptive networks in the central nervous system become hypersensitized to sensory inputs. During central sensitization astrocytes become highly reactive and release excitatory and synaptogenic factors that are required for nociceptive network sensitization. These astrocyte functions are regulated by Ca2+ signaling; however, the specific Ca2+ signaling mechanisms required in astrocytes for neuropathic pain are poorly understood. Astrocyte Ca2+ signaling involves somatic Ca2+ transients that traverse the entire cell body, and microdomain Ca2+ signals localized to thin astrocytic processes. Our functional understanding of these distinct astrocyte Ca2+ signals is limited by the complexity of mechanisms and channels that generate these signals in mammalian astrocytes. Our proposal will directly address this by taking advantage of recent seminal findings in Drosophila astrocytes demonstrating that somatic Ca2+ transients are mediated by the transient receptor potential (Trp) channel Waterwitch (Wtrw) and microdomain Ca2+ signals are mediated by TrpML channels. This provides us the means, for the first time, to genetically separate somatic and microdomain Ca2+ signals. We will combine this with a newly developed, adult Drosophila model of centrally mediated neuropathic pain. In Aim 1, we will determine how suppression of wtrw and trpml affects the development of neuropathic pain in adult Drosophila. In Aim 2, we will directly analyze somatic and microdomain Ca2+ signals in adult Drosophila astrocytes following acute injury. These experiments will allow us to clearly define the specific Ca2+ signaling mechanisms in astrocytes that drive neuropathic pain. This will represent an important breakthrough in our understanding of neuropathic pain etiology and may inform new pain therapeutic development.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
