Modified Intestinal apoAI-particles and Lymphatics Accelerate CKD-driven CVD

改良肠道 apoAI 颗粒和淋巴管加速 CKD 驱动的 CVD

• 批准号: 10544064
• 负责人: VALENTINA KON
• 金额: $ 43.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544064
• 关键词: Acceleration; Adverse effects; Affect; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Circulation; Clinical; Communication; Complement; Control Animal; Data; Development; Environment; Functional disorder; Generations; High Density Lipoproteins; Human; Indican; Inflammatory; Injury to Kidney; Intestines; Kidney; Kidney Diseases; Knock-out; Link; Lipids; Lipoproteins; Liver; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lysine; Mediator; Mesentery; MicroRNAs; Modification; Mus; Nerve; Organ; Organoids; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Plasma; Production; Proteins; Research; Role; Small Intestines; Small RNA; Source; Structure; Testing; Toxin; Uremia; Vascular Diseases; adduct; carbohydrate metabolism; dysbiosis; human disease; ileum; in vivo; intestinal epithelium; lymph flow; lymphatic dysfunction; lymphatic pump; lymphatic vessel; mesenteric lymphatics; microbial; oxidant stress; particle; perpetrators; protein metabolism; protein structure function; stem

Cardiovascular disease (CVD) has been linked to intestinal dysbiosis and chronic kidney disease, (CKD) disrupts the intestinal epithelial integrity and disturbs carbohydrate and protein metabolism that stimulate intestinal toxins. These toxins perpetuate the adverse effects through interorgan crosstalk known as the kidney-gut-cardiovascular axis that involves blood vessels and nerves. Our proposal challenges current research and clinical paradigms. We propose a new mediator and pathway in the kidney-gut-cardiovascular axis. The pathogenic mediator in the axis is intestinally-originating IsoLG-modified HDL. We hypothesize HDL, which is intestinally synthesized or filtered from the circulation, becomes modified by intestinally-generated IsoLG. The new pathway in the axis is the mesenteric lymphatic network that serves as a target and perpetrator for IsoLG-HDL effects by increasing propulsive mobility in these vessels and activating lymphatic endothelial cells. Together, the IsoLG-modified HDL and lymphatic vessels provide a sustained influx of intestinally-derived accelerants promoting vascular dysfunction and the development of atherosclerosis via the kidney-gut-cardiovascular axis. To test this hypothesis, we propose three mechanistic aims. In Aim 1, we will test the hypothesis that CKD-induced intestinal modification of HDL is a key pathogenic mechanism in the kidney-gut-cardiovascular axis. First, we will define the impact of kidney disease and uremic toxins on intestinal IsoLG production and modification of HDL. Next, we will use intestinal versus liver-specific knockouts of apoAI, the main structure-function protein of HDL, and ascertain how CKD impacts the contribution of intestinal- and plasma-derived HDL to the mesenteric lymph HDL pool. We will then determine the specific IsoLG modifications of apoAI in the CKD setting. We will also define the impact of CKD and IsoLG-modification on HDL-miRNA transport in plasma and mesenteric lymph. In Aim 2, we will test the hypothesis that IsoLG-modified HDL disrupts the structure and function of intestinal lymphatics in CKD. First, we will determine the impact of IsoLG-modified HDL on LEC phenotypic changes, vessel integrity, contractility, and lymphangiogenesis in CKD. We will then determine the role of HDL-miRNA in the interactions between HDL and the lymphatic network. We will first identify miRNA carried by lymphatic HDL in CKD. Then, we will determine the mesenteric lymphatic vascular network in humans with CKD and assess the link between CKD-HDL and dysfunction of lymphatic vessels and lymphatic endothelial cells. In Aim 3, we will test the hypothesis that CKD-driven acceleration in atherosclerosis can be reduced by IsoLG scavengers that lessen intestinal IsoLG-adducted lipoproteins and lymphatic dysfunction.

心血管疾病（CVD）与肠道营养不良和慢性肾脏疾病有关， （CKD）破坏肠上皮完整性并干扰碳水化合物和蛋白质代谢 刺激肠道毒素。这些毒素通过跨组织使不良反应永存 串扰，称为肾脏牙血管血管轴，涉及血管和神经。 我们的建议挑战当前的研究和临床范例。我们提出了一个新调解人 和肾脏甲状管血管轴的途径。轴中的致病介体为 无小的隔离式HDL。我们假设HDL是无关紧要的 从循环中合成或过滤的，通过无性生成的分离物进行了修饰。 轴上的新途径是肠系膜淋巴网络，它是目标和 通过增加这些容器的推​​进迁移率并激活 淋巴内皮细胞。共同修饰的HDL和淋巴管共同提供了 促进血管功能障碍和 通过肾脏刺激性血管轴发育动脉粥样硬化。为了检验这一假设， 我们提出了三个机械目标。在AIM 1中，我们将测试CKD诱导的假设 HDL的肠道修饰是肾脏甲状管血管中的关键致病机制 轴。首先，我们将定义肾脏疾病和尿毒症毒素对肠道肠的影响 HDL的生产和修改。接下来，我们将使用肠道与特定于肝的敲除 Apoai，HDL的主要结构功能蛋白，并确定CKD如何影响 肠道和血浆衍生的HDL对肠系膜淋巴HDL池的贡献。我们将 然后确定CKD设置中apoai的特定隔离修改。我们还将定义 CKD和分离式修饰对血浆和肠系膜中HDL-MIRNA转运的影响 淋巴。在AIM 2中，我们将测试以下假设：隔离的HDL破坏了结构和 CKD中肠道淋巴管的功能。首先，我们将确定Iselg修饰的影响 CKD中的HDL对LEC表型变化，血管完整性，收缩力和淋巴管生成。 然后，我们将确定HDL-MIRNA在HDL和淋巴之间相互作用中的作用 网络。我们将首先确定CKD中淋巴HDL携带的miRNA。然后，我们将确定 CKD的人类中的肠系膜淋巴血管网络，并评估 CKD-HDL和淋巴管和淋巴内皮细胞功能障碍。在AIM 3中，我们将 测试以下假设，即可以通过ISLEG降低动脉粥样硬化中的CKD驱动加速度 降低肠道分离的脂蛋白和淋巴功能障碍的清除剂。