Changes in the expression of the cannabinoid receptor 1 (CB1) has been associated with the progression of many human diseases such as anxiety and depression, schizophrenia, epilepsy, Huntington’s disease, Parkinson’s disease, obesity and osteoporosis. However, little is known about the mechanisms that control CB1 expression or how they may be affected by human polymorphic variation to bring about disease susceptibility. In order to elucidate the regulatory systems controlling the tissue specific transcriptional regulation of the CNR1 gene, that encodes CB1, and the effects of human polymorphisms on these systems, this study combined comparative genomics, molecular biology, cell biology and pharmacology with human genetics. Comparative genomics was used to identify five evolutionary conserved regions (ECR) 5’ of the CNR1 gene that had been conserved between humans and birds (310 million years). Primary cell culture, using luciferase reporter constructs and transgenic studies suggested that some of these regions acted as enhancers which controlled gene expression in a tissue specific manner. In addition, it was demonstrated that the activity of these ECRs can be altered using different signal transduction agonists. More importantly, evidence is provided to suggest that ECR1 and the endogenous CNR1 promoter work synergistically in primary dorsal root ganglia (DRG) neurons and that ECR2 and the CNR1 promoter work synergistically in primary hypothalamic neurons in response to MAPK and ER agonists. Furthermore, a validated human SNP within ECR1 can interfere with a putative AP-1 transcription factor binding site when the major allele is present to block the up-regulation seen with a MAPK agonist in hippocampal neurons. The discovery of such novel cell specific regulatory pathways and the recognition of the cell specific effects of polymorphisms on these pathways may lead to a better understanding of how CNR1 mis-expression can contribute to disease and will enhance our ability to develop novel therapies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:558592 |
| Date | January 2011 |
| Creators | Nicoll, Gemma Mhairi |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=186094 |
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