Mechanisms of Post-ganglionic Sympathetic Neuronal Excitability in Hypertension: Modulation by (360G-Wellcome-105409_Z_14_A)
Hypertension is characterised by enhanced cardiac sympathetic activity; a feature underpinned by aberrant neuronal intracellular calcium ([Ca2+]i) currents and enhanced neurotransmission at the end-organ 1,2. Increased [Ca2+]i is coupled to impaired nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling, and enhanced activity of voltage-gated Ca2+ (IcaN ) channels (Unpublished, Paterson). Why these ion channels have increased activity is not known. Additionally, recent evidence suggests that hypertension correlates with peripheral chemoreflex hypersensitivity and enhanced basal carotid body (CB) tonicity 3,4. Whether CB abnormalities develop prior to the onset of hypertension and indeed, underpin sympathetic hyperactivity remains to be determined. Molecular biology and fluorescence microscopy techniques will allow us to investigate dynamic signalling pathways and cellular adaptations in spontaneously hypertensive (SHR) versus normotensive Wistar rats. First, we aim to establish whether impaired cyclic nucleotide signalling within post-ganglionic sympathetic neurons (PSGNs) contributes to enhanced Ca2+-dependent exocytosis and the autonomic phenotype in hypertension, using both young pre-hypertensive and adult pro-hypertensive rats. Second, we aim to identify key molecular changes in type I cells which increase chemoreceptor sensitivity and investigate whether carotid sinus nerve ablation (CSA) rescues the sympathetic phenotype in hypertensive models. Third, we aim to combine pharmacological and genetic interventions to determine whether impaired NO-cGMP signalling is involved in abnormal chemoreflex responses in hypertension.
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Grant Details
Amount Awarded | 39578 |
Applicant Surname | Bardsley |
Approval Committee | Internal Decision Panel for C&S |
Award Date | 2016-09-30T00:00:00+00:00 |
Financial Year | 2015/16 |
Grant Programme: Title | PhD Studentship (Basic) |
Internal ID | 105409/Z/14/A |
Lead Applicant | Miss Emma Bardsley |
Partnership Value | 39578 |
Planned Dates: End Date | 2018-09-30T00:00:00+00:00 |
Planned Dates: Start Date | 2015-10-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | South East |
Sponsor(s) | Prof Stephen Tucker |