A CELL ATLAS OF THE DEVELOPING HUMAN SENSORY NERVOUS SYSTEM: INVESTIGATING DEVELOPMENT TO UNDERSTAND DISEASE

研究背景：疼痛是肌肉和关节疾病导致残疾的主要原因。特别是，对于数千万患有骨关节炎（OA）的人来说，疼痛在终末期可能会使人衰弱，甚至在休息时也会出现，从而阻止使用手，髋关节和膝关节。在世界各地，这种巨大的社会和货币负担将随着人口老龄化而上升。目前，没有治愈骨关节炎和终末期疾病的治疗与关节置换术，一个昂贵的和重大的手术。重要的是，我们缺乏有效的止痛药物治疗OA。直到最近，人们才认为关节保护层的磨损和骨与骨接触的增加是导致疾病疼痛的原因。有趣的是，最近来自不同研究小组的研究表明，新的神经作为OA疾病过程的一部分发芽到关节表面。这些神经似乎存在于疼痛性OA患者中，但在疼痛性OA较轻的患者中不存在。在成年期，神经通常具有有限的生长能力，因此这使我们认为，疾病神经是由类似于当我们的神经系统在子宫中胚胎开始发育时活跃的过程驱动的。因此，本项目的目的是应用尖端技术来研究人类感觉神经的发育，将其与疾病中发生的情况进行比较，目的是确定干预它的新方法，以治疗疼痛。目的和目标：首先，我们的目标是了解感觉神经系统在发育中的人类中是如何形成的。为了实现这一目标，我们将使用单细胞测序技术。这将使我们能够逐一检测驱动不同类型神经发育的因素。我们的目标是为这些神经建立一个分类系统，按照它们的功能进行分类，例如，一些神经可以感知触摸，另一些可以感知疼痛，它们可能受到不同信号的驱动而生长。其次，我们将使用一种称为空间转录组学的技术来绘制这些发育中的神经在空间中的分布。这将形成整个身体的神经图谱，并使我们能够了解神经在发育过程中如何排队向其目的地生长。然后，我们将绘制成人骨关节炎患者膝关节中的神经。我们将应用创新技术，首先确定神经存在的区域，然后对这些区域内激活的基因进行测序。这将使我们能够了解在疾病中生长的神经与在发育过程中生长的神经是否相似或不同。最后，我们将使用计算程序来比较发育神经和疾病神经。这将使我们能够决定如何靶向疾病神经。潜在的应用和好处：我们将是第一个对人类发育中的神经系统进行单细胞测序的团队。这将允许发现新的细胞类型，并为它们在整个人体中创建一个图谱。这些发现将进一步加深我们对所有疼痛状况的理解。在骨关节炎的情况下，它可以让我们确定可以利用的目标，以允许耗尽上述疼痛相关的神经。我们的目标是传播我们的研究结果，让公众访问的研究界。这将有助于我们更好地理解其他疾病，例如癌症，在疾病过程中神经也会发芽。从长远来看，我们的发现也可以用于帮助改进实验室中生长的神经模型，并可能为促进神经在体内再生的方法提供信息。

Context of the research:Pain is the main reason that diseases of the muscles and joints lead to disability. In particular, for the tens of millions of individuals who suffer from Osteoarthritis (OA) , pain can be debilitating at end stages and be present even at rest, preventing the use of joints in the hand, hip and knees. Around the world, this tremendous societal and monetary burden is set to rise alongside an aging population. Currently, there is no cure for osteoarthritis and end stage disease is treated with joint replacement, a costly and major operation. Importantly, we lack effective pain-relief medications for OA.Until recently, it was thought that wear-and-tear of the protective lining of the joint, and increased bone-to-bone contact is what leads to pain in disease. Interestingly, recent studies from various research groups have shown that new nerves sprout into the joint surface as part of the disease process of OA. These nerves appear to be present in individuals with painful OA, but is absent in those with less painful OA. In adulthood, nerves normally have limited capacity to grow, so this leads us to think that disease nerves are driven by processes similar to those that are active when we our nervous system begins to develop while an embryo in the womb. The objective of this project is therefore to apply cutting edge technology to investigate the development of the human sensory nervous, comparing it to what happens in disease, with the aim of identifying novel ways of interfering with it, in order to treat pain.Aims and objectives:First, we aim to understand how the sensory nervous system forms in the developing human. To achieve this, we will use single-cell sequencing technologies. This will allow us to detect what drives different types of developing nerves, one by one. We aim to form a classification system for these nerves, sorting them by their function, for example, some nerves may sense touch and others may sense pain, and they might be driven by different signals to grow.Secondly, we will map the distribution of these developing nerves in space, using a type of technology known as spatial transcriptomics. This will form an atlas of the nerves throughout the body and allow us to understand how nerves are queued to grow towards their destination during development. Then, we will map nerves in the diseased human osteoarthritic knee joint in adulthood. We will apply innovative technologies to first identify areas where nerves are present, and then sequence the genes activated within these areas. This will allow us to understand whether nerves growing in disease are similar or different to nerves that grow during development.Lastly, we will use computational programs to compare developmental nerves to disease-nerves. This will allow us to decide how to target the disease-nerves.Potential applications and benefits:We will be the first group to perform single-cell sequencing on the developing nervous system in human. This will allow discovery of new cell-types, and create an atlas for them throughout the human body. These findings will further our understanding of all painful conditions. In the case of osteoarthritis, it may allow us to identify targets that can be exploited to allow depletion of the pain-associated nerves described above. We aim to disseminate our findings to allow public access by the research community. This will lead to improved understanding of other diseases, such as in cancer, where nerves can also sprout during the disease process.In the long term, our findings can also be applied to help improve models of nerves grown in the laboratory, and potentially also inform ways of promoting nerves to regenerate in the body.