Pulmonary Neurobiology
Laboratory
Research Projects
 ..... 
Peripheral
neuropathy and pain: Role of the sphingosine kinase/sphingosine
1-phosphate system
Our preliminary data using rodent dorsal root ganglia and spinal cord show that S1P induced hyperalgesia acting via S1P1 receptors situated on peripheral nociceptors. This algesic action of S1P together with its well known immunmodulatory role strongly points to S1P and its receptors as a significant new target for analgesic and anti-inflammatory therapy for peripheral neuropathic pain.
The project aims to test the hypotheses that:
- Components of the sphingosine kinase/sphingosine 1-phosphate signalling pathway are expressed selectively by nociceptive spinal sensory neurons
- The activity of sphingosine kinases(SK) and receptor-mediated responses to sphingosine 1-phosphate in nociceptive neurons lead to neuropathic pain
- The dysregulation of the SK/S1P signalling pathway in nociceptive neurons can be inhibited by blockade of miRNAs selective for components of the SK/S1P signalling pathway.
Function of microRNAs in nociceptive neurons in dorsal root ganglia and spinal cord
MicroRNAs (miRNAs) are small non-coding RNAs that regulate diverse biological functions by post-transcriptional repression or degradation of target mRNAs. It is predicted that up to two thirds of protein coding genes are regulated by miRNAs [19]. Many miRNAs lie within introns of protein-coding genes and are commonly transcribed by RNA polymerase II. Critically, a single variety of miRNA can regulate up to 200 target mRNAs. Thus miRNAs are prime candidates as regulators of mRNA translation in nociceptors.
The long distance between the cell body of nociceptive neurons and their peripheral and central nerve endings requires high rates of mRNA and protein turnover and their associated axonal transport. Since a given miRNA regulates expression of hundreds of target mRNAs, neuronal miRNAs provide an extremely powerful mechanism to dynamically adjust the protein content of neuronal compartments without requiring new gene transcription. This together with the lack of correlation between mRNA expression and protein levels in peripheral nociceptors in response to noxious stimuli, leads to our overall hypothesis that:
- MicroRNAs coordinate altered mRNA and protein levels in nociceptive neurons. Differences in the miRNA expression profile in nociceptive neurons determine the susceptibility to noxious stimuli and underlie the development of chronic pain in response to peripheral injury and inflammation.
Sphingosine 1-phosphate signalling in asthma and COPD: impact on lung vasculature and macrophage function
Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory airway disorders. However, the characteristic inflammation in both is not restricted to the airways, but also affects pulmonary vessels. Airways from patients who die during an asthma attack show inflammation extending to large pulmonary arteries adjacent to bronchi.
Inflammatory mechanisms also contribute to alterations of the pulmonary circulation and the development of pulmonary hypertension in COPD. In COPD, the structural and functional changes in the pulmonary vasculature are associated with shorter survival rates whereas for asthma no data are available. Our preliminary studies in murine models show that absence of sphingosine kinase-1 (SK1) leads to dysfunction of peripheral airways and the pulmonary vasculature accompanied by vascular remodelling, as well as significant changes in the inflammatory response with increased macrophage numbers and cytokine expression levels in the lung. Importantly, the structural changes in the pulmonary vasculature and the increase in macrophage numbers resemble those noted in COPD. Therefore, the project aims to test our hypotheses that:
- Modulation of the sphingosine kinase/sphingosine 1-phosphate signal transduction pathway is a characteristic feature of asthma and COPD
- Cell-type specific modulation of the sphingosine kinase/sphingosine 1-phosphate signal transduction pathway is important for vascular and macrophage function and thus, a promising target for treatment of patients with asthma or COPD.
<Back to Pulmonary Neurobiology Home
Page >
|
