Identifying novel mechano-receptors in the sensory nervous system

哺乳动物如何察觉钝力或尖锐物体的有害性质？身体是如何防御性地增加受伤或发炎组织的敏感性，使原本无害的动作和触摸感到疼痛的？作为衰老不可避免的后果，后一个过程是如何随着时间的推移而出现问题，造成沉重的慢性疼痛的？最后一个问题尤其紧迫，因为它对个人和社会都有巨大的影响。要回答这些问题，我们必须看看感觉神经。这些细胞为我们的器官（包括皮肤）提供检测外部和内部环境的物理和化学性质信息的能力。它们通过一种叫做受体的蛋白质分子来做到这一点，这种蛋白质分子可以检测到特定类型的环境线索，并引发反应。在过去的十年中，我们已经了解了很多关于这些机械激活（MA）受体的身份。发现了一类名为Piezos的新受体。在感觉神经中，这些神经负责探测轻触和肢体的位置（本体感觉）。它们还复杂地参与感知我们内部器官中产生的各种压力和拉伸。其他MA受体的身份，其中包括那些检测疼痛触摸和对损伤或炎症反应增加的机械敏感性的受体，在很大程度上仍然未知。揭示这些受体的身份是一项具有挑战性的任务，而且有很高的回报。这一发现将极大地扩展我们对触觉的认识，并为开发更好的止痛药物提供新的目标。在本提案中，我们通过采用双管齐下的方法来应对这一挑战，两者都集中在寻找这些重要受体的预期结果上。首先，我们将搜索整个人类基因组，以确定使机械受体功能的受体。这是通过我们开发并验证的新方法实现的，称为TAGS。第二种方法涉及比较两个非常相似（几乎相同）的神经细胞群，每个都参与检测机械信号，其中一个我们发现在更高水平上有未知的MA受体。这种比较使我们能够生成一个高概率候选列表，我们将在这里测试以确定这些神经中正确的受体。这两种方法的结合使用将使我们能够成功地识别新的MA受体分子，这将为疼痛研究领域带来重要的进展。

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.