EXAMINING THE ROLE OF GUT DYSBIOSIS IN OBSTRUCTIVE SLEEP APNEA INDUCED HYPERTENSION.

项目总结： 阻塞性睡眠呼吸暂停(OSA)是系统性高血压和其他心血管疾病的重要危险因素 疾病。虽然这种关系已经牢固地建立起来，但对OSA如何导致 人们对高血压知之甚少。最近，科学家们开始认识到神经炎是一种 高血压发展的重要因素，包括与阻塞性睡眠呼吸暂停综合征相关的高血压。然而， 阻塞性睡眠呼吸暂停综合征的潜在来源和非法神经炎症的步骤尚不清楚。在这项提案中，我们将 形成肠道微生物区系负责启动和维持所需的神经炎症的想法 用于高血压的发展。近年来，人们认识到微生物区系-肠道-脑轴 存在，因此肠道中的微生物在调节大脑动态平衡和 功能。我们提出了OSA促进神经炎症和高血压的总体假设 通过肠道生物失调和微生物区系-肠道-脑轴的改变。我们已经找到了 初步研究表明，阻塞性睡眠呼吸暂停综合征会改变肠道微生物区系的组成，导致肠道屏障破坏， 将细菌和内毒素引入体循环。我们还表明，OSA促进了 肠道和大脑中先天免疫细胞的促炎表型。此外，我们还联系了OSA- 通过证明高血压表型可以通过诱导生物失调而发展为高血压 通过移植一种非生物微生物群转移到血压正常的大鼠身上。最后，我们提供了基础 对于一种使用口服益生菌和益生菌的治疗策略，这两种益生菌能够防止微生物失调，减少肠道 抑制炎症和神经炎症，预防阻塞性睡眠呼吸暂停综合征引起的高血压。这项提议的主要目标是 为了了解OSA如何改变微生物区系-肠道-脑轴的组成部分，并对 神经炎症和高血压，重点是激活的免疫细胞信号(目标1)，改变的代谢物 信号传递(目标2)和预防OSA诱发高血压的方法(目标1-3)。在每个目标中，我们都会 通过饮食或下一代益生菌操纵微生物组，以确定对OSA诱导的影响 高血压，一种在我们超重和老龄化人口中变得越来越常见的疾病。

Project Summary: Obstructive sleep apnea (OSA) is a significant risk factor for systemic hypertension and other cardiovascular diseases. While this relationship has been firmly established, an understanding of how OSA leads to hypertension is poorly understood. Recently, scientists have begun to recognize that neuroinflammation is an important factor in the development of hypertension, including that hypertension associated with OSA. However, the underlying source and the steps that illicit neuroinflammation with OSA is unknown. In this proposal, we will develop the idea that the gut microbiota is responsible for initiating and maintaining neuroinflammation required for the development of hypertension. In recent years, it has been recognized that a microbiota-gut-brain axis exists, whereby microorganisms residing in the gut play a critical role in regulating brain homeostasis and function. We propose the overall hypothesis that OSA promotes neuroinflammation and hypertension through gut dysbiosis and modification of the microbiota-gut-brain axis. We have found through preliminary studies that OSA alters the makeup of the gut microbiota, leads to gut barrier disruption and the introduction of bacteria and endotoxins into the systemic circulation. We have also shown that OSA promotes a pro-inflammatory phenotype in innate immune cells in both the gut and brain. Additionally, we have linked OSA- induced dysbiosis to the development of hypertension by demonstrating that the hypertensive phenotype can be transferred to a normotensive rat by transplantation with a dysbiotic microbiota. Lastly, we provide the foundation for a therapeutic strategy using oral prebiotics and probiotics, which were able to prevent dysbiosis, reduce gut inflammation and neuroinflammation, and prevent OSA-induced hypertension. The main goal of this proposal is to understand how components of the microbiota-gut-brain axis are altered by OSA and contribute to neuroinflammation and hypertension, with a focus on activated immune cell signaling (Aim 1), altered metabolite signaling (Aim 2), and methods of preventing OSA-induced hypertension (Aims 1-3). In each aim we will manipulate the microbiome by diet or next generation probiotics to determine the effects on OSA-induced hypertension, a disease becoming more common in our overweight and aging population.