Investigating novel mechanical receptors in the sensory nervous system

研究感觉神经系统中的新型机械受体

• 批准号: 2739537
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2739537
• 关键词: Investigating; novel; mechanical; receptors; sensory

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.

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？作为衰老的必然结果，后一个过程是如何随着时间的推移而出错的，从而产生负担沉重的慢性疼痛的？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）提供检测环境物理和化学性质信息的能力。它们是通过一种叫做受体的蛋白质分子来实现这一目的的，这种蛋白质分子被调整以检测特定类型的环境线索。在过去的十年里，我们已经了解了很多关于感受器的知识，这些感受器可以感知热、冷和轻触。然而，那些对触摸疼痛负责的人仍然难以捉摸。发现和表征这些分子会带来很高的回报。除了增进我们对感觉生理学的了解外，这些研究还将为开发新的、更有效的、副作用更少的止痛疗法提供潜在的靶点。本研究计划将利用功能基因组学及电生理学的最新技术来鉴定及研究这类蛋白质，其总体目标是在感觉神经系统中鉴定新的分子受体，特别是针对有害机械刺激的分子受体。该项目将通过两种平行和互补的方法实现这一目标。首先，我们将通过高效转染方法将活性依赖性荧光构建体递送到感觉神经中，以基于其表型选择性地标记这些神经元。这些神经元的基于表型的富集和收集之后将进行比较表达谱分析，产生在表型阳性神经元中富集的差异表达基因列表，其将进行二次检测。第二种方法将应用实验室开发的新型全基因组筛选技术。这利用异源表达系统通过随机基因激活诱变来鉴定这种新型机械活化蛋白质。这两种平行的方法将相互补充，并产生显着的新的洞察力的分子基础的机械转导。