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，使原本无害的运动和触摸感到疼痛？作为衰老的不可避免的结果，后一个过程如何随着时间的推移而出错，从而产生难以忍受的慢性疼痛？最后一个问题特别紧迫，因为它对个人和社会都造成了巨大的损失。为了回答这些问题，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。它们通过被称为受体的蛋白质分子来做到这一点，这些蛋白质分子被调谐以检测特定类型的环境线索，并触发反应。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。发现了一类新的受体，命名为Piezos。在感觉神经中，这些神经负责检测轻触以及我们四肢的位置（本体感觉）。它们还复杂地参与感知我们内脏器官中出现的各种压力和拉伸。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的机械敏感性增加的受体，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，具有很高的回报。这一发现将极大地扩展我们对触觉的了解，并为开发更好的止痛药物提供新的目标。在这项提案中，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，每个神经细胞群都参与检测机械线索，其中一个神经细胞群我们发现具有更高水平的未知MA受体。这种比较使我们能够生成一个高概率候选者的列表，我们将在这里进行测试，以识别这些神经中的正确受体。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.