Pathophysiological relevance of the chemosensory channel TRPA1 regulation by cholesterol reducing medications.

Cholesterol is a bioactive lipid that contributes to the structural stability of signaling hubs in cellular membranes. Unhealthy live styles and genetic defects leading to cholesterol dysregulation can result in life-threatening cardiovascular diseases with a huge societal impact. A mainstream treatment against these conditions is the inhibition of cholesterol synthesis by statins. However, these drugs can have serious side effects as paresthesia, sensory loss, chronic pain, and inflammation through the induction of poorly understood neuropathies. TRPA1 is a cation channel that senses multiple noxious chemical and thermal stimuli and is implicated in a plethora of pain and inflammatory conditions. We recently reported that cholesterol modulates TRPA1 expression and activation and preliminary experiments show that TRPA1 function is modulated by statins. In this project, we will test the hypothesis that TRPA1 mediates noxious sensory side effects of statins. We will determine the effects of these compounds on the expression pattern and activation of this channel and elucidate the underlying molecular mechanisms. We will also conduct a variety of in vitro, in situ, and in vivo experiments in mice to assess sensory neuron functions to test TRPA1 implication in pain and inflammation under acute and long-term statin treatments. This work will serve to determine whether TRPA1 may be used as a therapeutic target against the noxious effects associated with the clinical use of statins.