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

项目摘要： 阻塞性睡眠呼吸暂停（OSA）是全身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 对高血压知之甚少。最近，科学家们开始认识到，神经炎症是一种 高血压发展的重要因素，包括与OSA相关的高血压。然而，在这方面， 导致阻塞性睡眠呼吸暂停综合征的潜在原因和步骤尚不清楚。在本提案中，我们将 发展肠道微生物群负责启动和维持所需的神经炎症的想法 导致高血压的发生近年来，已经认识到微生物群-肠-脑轴 存在，由此驻留在肠道中的微生物在调节脑内稳态中发挥关键作用， 功能我们提出的总体假设是，OSA促进神经炎症和高血压 通过肠道生态失调和微生物群-肠-脑轴的改变。我们发现， 初步研究表明，OSA改变了肠道微生物群的组成，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 肠和脑中先天免疫细胞的促炎表型。此外，我们还将OSA- 通过证明高血压表型可以是 通过与生态失调的微生物群一起移植转移到血压正常的大鼠。最后，我们提供基础 对于使用口服益生元和益生菌的治疗策略，它们能够防止生态失调，减少肠道 炎症和神经炎症，并预防OSA引起的高血压。该提案的主要目标是 了解微生物-肠-脑轴的组成部分如何被OSA改变，并有助于 神经炎症和高血压，重点是激活免疫细胞信号传导（Aim 1），改变代谢产物 信号传导（目的2）和预防OSA诱导的高血压的方法（目的1-3）。在每一个目标，我们将 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 高血压，一种在我们超重和老龄化人口中越来越常见的疾病。

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.