Understanding and enhancing repair of the tympanic membrane

听觉作为人类的五种感官之一，不仅对交流，而且对我们的生活质量和融入社会都很重要，影响着言语和语言技能。我们之所以能够听到，是因为耳朵这一独特而复杂的听觉器官。耳朵分为三个部分，外耳(耳廓和耳道)，中耳(有三块小骨头)和内耳，毛细胞在内耳感知振动并将信息传输到大脑。外耳和中耳之间有鼓膜，这是一种将声波转化为振动的薄而透明的膜。这种膜很容易受到耳部感染、压力变化或头部创伤造成的损害。据认为，30%的儿童会因为急性耳炎(胶耳或中耳炎)而导致鼓膜破裂。膜上的大部分孔洞在没有任何干预的情况下很快愈合。然而，有些洞不会愈合，导致耳朵疼痛、耳鸣(耳鸣)、耳朵感染和听力丧失。这些无法愈合的穿孔被称为慢性穿孔，可能是由于最初损伤的大小或位置，或感染性因素的存在。这种慢性穿孔必须通过手术将身体其他部位的组织移植到耳朵中来弥合缺口。目前还不清楚耳鼓如何愈合。有人提出，成体干细胞存在于耳朵中，能够帮助耳洞的再生和愈合。研究表明，这些干细胞位于鼓膜的不同部分，在边缘(耳环)和鼓膜与中耳骨相接的中心(耳柄)。添加干细胞或刺激修复途径的信号分子已被认为是治疗慢性穿孔的潜在方法。我们计划使用现代成像技术、转基因小鼠模型和新的培养技术来解决围绕鼓膜穿孔修复的一些问题。主要的申请者塔克教授是中耳方面的专家，而她的合作者保罗·马丁教授则提供了他在上皮伤口愈合方面的经验，以创建一个解决严重临床问题的独特研究项目。我们首先旨在通过跟踪损伤后耳朵中的干细胞及其后代，并通过干扰一些被认为在修复中起作用的过程(细胞迁移、增殖、血管形成)来确定修复过程中发挥作用的机制。接下来将对控制鼓膜干细胞的信号进行分析，重点研究Wnt信号的作用。WNTs是一个信号分子家族，在体内许多其他组织的干细胞维持和修复中起着至关重要的作用。在推测的鼓膜干细胞巢中发现了WNT活性，但目前对这一途径在耳膜中的作用一无所知。我们将研究增强和抑制Wnt信号对鼓膜愈合能力的影响。最后，我们将使用我们的外植体培养模型来了解当前的治疗方法，如局部应用FGF2，实际上是如何起作用的。该项目采用了一种新的方法(耳鼓的外植体培养)，以便在耳朵愈合时对其进行可视化，并旨在为创造新的创新方法来预防未来的慢性穿孔提供基础。

Hearing as one of the five human senses is important not only for communication but also for our quality of life and integration into society, impacting on speech and language skills. We are able to hear due the unique and complex hearing organ that is the ear. The ear is divided into three parts, the external ear (pinna and ear canal), middle ear, with its three little bones, and inner ear, where the hair cells sense vibrations and transfer information to the brain. In between the external and middle ear sits the ear drum, a thin transparent membrane that converts sound waves into vibrations. This membrane is very susceptible to damage caused by ear infections, pressure changes or head trauma. Its thought that 30% of children will suffer from breaks in their ear drum caused by acute ear inflammation (glue ear or otitis media). Most holes in the membrane heal rapidly without any intervention. Some holes, however, do not heal leading to ear pain, ringing in the ears (tinnitus), ear infections, and hearing loss. These perforation that fail to heal are called chronic and may be due to the size or position of the initial damage, or the presence of infectious agents. Such chronic perforations have to be corrected using surgery with tissue from elsewhere in the body grafted into the ear to bridge the gap.How the ear drum is able to heal is unclear. It has been proposed that adult stem cells reside in the ear and are able to aid in regeneration and healing of holes. Research suggests that these stem cells are located in distinct parts of the ear drum, at the border (the annulus) and in the centre where the ear drum meets the middle ear bones (manubrium). Addition of stem cells, or signaling molecules that can stimulate repair pathways have been suggested as potential treatment for chronic perforations.We plan to use modern imaging techniques, transgenic mouse models, and novel culture techniques to address some of the questions surrounding repair of ear drum perforations. The lead applicant, Prof Tucker, is an expert on the middle ear, while her collaborator, Prof Paul Martin, provides his experience of epithelial wound healing, to create a unique research project that tackles a serious clinical problem.We first aim to determine the mechanisms at play during repair by following stem cell populations and their progeny in the ear after injury, and by perturbing some of the processes (cell migration, proliferation, vascularization) that are thought to play a role in repair. This will be followed by an analysis of the signals that control the ear drum stem cells, concentrating on the role of Wnt signaling. Wnts are a family of signaling molecules with essential role in stem cell maintenance and repair in many other tissues in the body. Wnt activity is found in the putative ear drum stem cell niche but nothing is currently known about the role of this pathway in the ear drum. We will look at the effect of enhancing and inhibiting Wnt signaling on the ability of the ear drum to heal.Finally we will use our explant culture model to understand how current therapeutics, such as topical application of Fgf2, actually work. The project takes a new approach (explant culture of the ear drum) to allow visualization of the ear as it heals and aims to provide the groundwork to create new and innovative ways to prevent chronic perforations in the future.