Friday, July 26, 2024
7/26/2024
Abstract/Summary Examining the mechanistic interactions between K channels’ dysfunction in rNLS8 mice. Clinical Relevance: Current amyotrophic lateral sclerosis (ALS) treatments only produce modest increases in lifespan and little-to-no symptom relief. As motoneuron (MN) excitability dysfunction is an early and persistent feature of ALS, it is believed to contribute to MN degeneration. Pilot data from the parent grant indicates key roles for Kv2.1 and SK channels in MN excitability dysfunction. Both channels are colocalized, are commonly activated by Ca, receive common input from C-boutons, and, importantly, mediate K ion currents. These traits, and our pilot data, suggest a functional interaction between SK and Kv2.1 channels. The objective of this research is to identify and characterize previously unknown interactions between Kv2.1 and SK channels. We will study these in both normal and dysfunctional conditions, using the rNLS8 mouse model of ALS. Rationale: These channels both regulate excitability and are altered in ALS, and are thus likely involved in dysregulation of excitability in ALS. SK and Kv2.1 have been studied separately, and few studies examine Kv2.1 in the spinal cord. Given their roles in excitability regulation, it is critical that we characterize these overlooked channel interactions and their roles in ALS, which will expand the parent grant’s results. Thus, our Supplement Specific Aims are to test the interdependence of these K channels’ activation in healthy vs rNLS8 MNs. Functional dependencies of either channel on the other in health would represent novel mechanistic knowledge. Moreover, a change in these interactions within the disease model would also represent novel mechanisms which would become novel candidates for therapeutic targets. Completion of these studies will elucidate the mechanisms of Kv2.1 and SK dysfunctions in ALS.
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).
