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

心血管疾病（CVD）与肠道生态失调和慢性肾脏疾病有关， (CKD)破坏肠上皮的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器官间的相互作用， 肾-肠-心血管轴的相互作用，涉及血管和神经。 我们的提案挑战了当前的研究和临床范式。我们提议一个新的调解人 以及肾-肠-心血管轴中的通路。轴中的致病介质是 血管源性IsoLG修饰的HDL。我们假设高密度脂蛋白 合成或从循环中过滤出来，被体内产生的IsoLG修饰。 轴中的新途径是肠系膜淋巴网络，其作为靶点， 通过增加这些血管的推进流动性和激活 淋巴管内皮细胞总之，IsoLG修饰的HDL和淋巴管提供了一种新的途径。 持续流入的血管衍生促进血管功能障碍和 通过肾-肠-心血管轴发展动脉粥样硬化。为了验证这个假设， 我们提出三个机械目标。在目标1中，我们将检验CKD诱导的 HDL的肠道修饰是肾-肠-心血管疾病的关键致病机制， 轴线首先，我们将确定肾脏疾病和尿毒症毒素对肠道IsoLG的影响。 HDL的生产和修饰。接下来，我们将使用肠道与肝脏特异性敲除 apoAI是HDL的主要结构-功能蛋白，并确定CKD如何影响HDL的功能。 肠源性和血浆源性HDL对肠系膜淋巴HDL池的贡献。我们将 然后确定CKD背景下apoAI的特异性IsoLG修饰。我们还将定义 CKD和IsoLG修饰对血浆和肠系膜HDL-miRNA转运的影响 淋巴管在目标2中，我们将检验IsoLG修饰的HDL破坏结构并 肠蠕动在CKD中的作用。首先，我们将确定IsoLG修饰的 HDL对CKD患者LEC表型变化、血管完整性、收缩性和淋巴管生成的影响 然后我们将确定HDL-miRNA在HDL和淋巴细胞相互作用中的作用。 网络我们将首先鉴定CKD中淋巴HDL携带的miRNA。然后，我们将确定 慢性肾脏病患者肠系膜淋巴管网络，并评估 CKD-HDL与淋巴管和淋巴管内皮细胞功能障碍。在目标3中，我们 测试假设CKD驱动的动脉粥样硬化加速可以通过IsoLG降低 清除剂，减少肠道IsoLG-加合脂蛋白和淋巴功能障碍。

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.