Investigating novel mechanical receptors in the sensory nervous system

点击翻译按钮获取中文摘要

How do mammals detect the harmful nature of blunt force, or sharp objects?How does the body defensively increase sensitivity of injured or inflamed tissues, making otherwise innocuous movements and touch feel painful? And how, as an inevitable consequence of aging, does the latter process go wrong over time, creating burdensome chronic pain? To answer these questions, we must look at sensory nerves. These cells supply our organs (including the skin) with the ability to detect information about the physical and chemical nature of our environments. They do so via protein molecules called receptors, tuned to detect specific types of environmental cues. In the past decade we havelearned much about receptors that detect heat, cold, and light touch. Those responsible for painful touch, however, remain elusive. Uncovering and characterizing these molecules carries a high reward. Beyond furthering our knowledge of sensory physiology, these would provide potential targets for the development of new, more effective pain-relief therapies with fewer side-effects. This project will use state-of-the-art technologyin functional genomics and electrophysiology to identify and study such proteins.The overall goal of the project is the identification of novel molecular receptors within the sensory nervous system, with a particular focus on those of noxious mechanical stimuli. The project will deliver this goal by two parallel and complementary approaches. First, we will deliver activity-dependent fluorescent constructs into sensory nerves via a high-efficiency transfection method to selectively label these neurones based on their phenotype. Phenotype-based enrichment and collection of these neurons will be followed by comparative expression profiling, yielding a list of differentially expressed genes enriched in phenotypically positive neurons which will be subject to secondary testing. The second approach will apply novel genome-wide screening technology developed in the lab. This utilises heterologous expression systems for the identification of such novel mechanically activated proteins via random, gene-activating mutagenesis. These two parallel approaches will complement each other and yield significant novel insight into the molecular underpinning of mechanotransduction.