Identifying novel mechano-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? The last question is especially pressing due to the massive toll it exerts on both individuals and society. To answer these questions, we must look at sensory nerves. These are cells that supply our organs (including the skin) with the ability to detect information about the physical and chemical nature of the outer and inner environments. They do so via protein molecules called receptors, tuned to detect specific types of environmental cues, and trigger a response. In the past decade we have learned much about the identity of these mechanically activated (MA) receptors. A new class of receptors named Piezos were identified. In sensory nerves, these are responsible for detecting light touch as well as the position of our limbs (proprioception). They are also intricately involved in sensing various kinds of pressure and stretch that arise in our internal organs. The identity of other MA receptors, among them those that detect painful touch and increased mechanical sensitivity in response to injury or inflammation, are still largely unknown. Uncovering the identity of these receptors is a challenging task that carries a high reward. Such a discovery would greatly expand our knowledge about tactile sensation, and present new targets for the development of better pain-relieving medication. In this proposal we take on this challenge by applying a two-pronged approach, both converging on the desired outcome of finding these important receptors. First, we will search the entire human genome to identify receptors that enable mechano-receptor function. This is made possible by the new method we developed, and validated, called TAGS. The second approach involves comparison of two very similar (near-identical) nerve cell populations, each involved in detecting mechanical cues, and one of which we have found to have unknown MA receptors at a much higher level. This comparison has allowed us to generate a list of high-probability candidates, which we will test here to identify the correct receptors in these nerves. The combined use of these two approaches will enable us to successfully identify new MA receptor molecules, which will deliver important advances to the field of pain study.