COCHLEAR MACROPHAGES AND EPITHELIAL REPAIR

 描述（由申请人提供）：在内耳中，将氧气和营养物质输送到听觉细胞的血管受到仔细调节，使得血管内的液体不会泄漏到内耳的组织中。血液内容物和内耳内容物之间的这种分离称为血液-外淋巴屏障。这种屏障调节免疫系统，并控制白色血细胞从血流进入器官的交通。当免疫系统被激活时，白色血细胞可以离开血管，进入靶器官并消除有害细菌或不需要的细胞，但同时，它可以损害不是预期目标的健康组织。因此，仔细调节这一屏障和免疫反应非常重要。在某些情况下，当屏障变得泄漏时，来自血管的液体和溶质与内耳液体混合，这种混合被认为会导致听力损失，尽管这尚未得到证实。在我们的第一系列实验中，我们将确定血管通透性如何影响听力。我们的目标是了解这种障碍的破坏如何影响听力水平，以及如何修复和保留听力。我们的第二系列研究将集中在脑膜炎期间进入耳蜗的特定白色血细胞的作用。脑膜炎是一种危及生命的感染， 脊髓液和内耳液，其中血-外淋巴屏障和血-脑屏障严重受损。脑膜炎通常与永久性听力损失有关，有时还与耳蜗骨化有关，即在通常充满液体的空间中形成新骨。耳蜗骨化是一个主要问题，因为耳蜗植入物是我们治疗耳聋的最佳工具，当植入物的空间被骨填充时，通常无法放置。我们认为，对感染的免疫反应导致这种新骨形成，并导致听力损失。虽然免疫反应是必不可少的，以消除感染脑膜炎，更好地控制免疫反应可能会导致保留听力。如果我们能够预防脑膜炎患者的听力损失，并防止脑膜炎后耳蜗中新骨的形成，这将极大地帮助受这种情况影响的人的健康。该补助金的总体目标是提高我们对免疫系统如何与内耳环境相互作用的理解，免疫系统的哪些部分是有益的，例如预防或消除感染，以及其功能可能是有害的。由于目前许多听力损失的治疗方法都涉及使用抑制免疫系统的药物，因此了解免疫系统如何在内耳中工作，设计更好的药物并提高听力损失治疗的有效性非常重要。

 DESCRIPTION (provided by applicant): In the inner ear, the blood vessels that carry oxygen and nutrients to the hearing cells are carefully regulated so that fluids inside the blood vessel d not leak into the tissues of the inner ear. This separation between contents of the blood and contents of the inner ear is called the blood-perilymph barrier. This barrier regulates the immune system and controls the traffic of white blood cells from the blood stream into the organs. When the immune system is activated, white blood cells can leave the vessels, enter the target organ and eliminate harmful bacteria or unwanted cells, but at the same time, it can damage healthy tissues that were not the intended targets. Therefore, careful regulation of this barrier and the immune response are very important. Under certain conditions, when the barrier becomes leaky, fluids and solutes from the blood vessels mix with the inner ear fluids, and this mixing is believed to cause hearing loss, although this has not been proven. In our first series of experiments, we will determine how vessel permeability affects hearing. Our goal is to understand how disruption of this barrier influences hearing levels and how it can be repaired and hearing be retained. Our second series of studies will focus on the role of specific white blood cells that enter the cochlea during meningitis. Meningitis is a life-threatening infection of the spinal fluid and inner ear fluid where the blood-perilymph barrier and the blood-brain barrier are severely compromised. Meningitis is commonly associated with permanent hearing loss and sometimes with cochlear ossification, where new bone forms in the spaces that are normally fluid-filled. Cochlear ossification is a major concern because cochlear implants, which are our best tool for treating deafness, often cannot be placed when the space for the implant is filled with bone. We believe that the immune response to infection results in this new bone formation and contributes to hearing loss. Although the immune response is essential to eliminate the infection in meningitis, better control of the immune response may result in preserved hearing. If we could prevent the loss of hearing in patients with meningitis and prevent the formation of new bone in the cochlea after meningitis, it would greatly help the well being of people who are affected by this condition. The overall goals of this grant are to improve our understanding of how the immune system interacts with the inner ear environment, what parts of the immune system are beneficial, such as preventing or eliminating infections, and which of its functions might be harmful. Because many current therapies for hearing loss involve the use of medications that suppress the immune system, it is important to understand how the immune system works in the inner ear, to design better medications and improve the effectiveness of treatment for hearing loss.