Harnessing Neu5Gc sialidases to treat Neu5Gc-associated atherosclerosis

利用 Neu5Gc 唾液酸酶治疗 Neu5Gc 相关的动脉粥样硬化

• 批准号: 10364599
• 负责人: Joanna Coker
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364599
• 关键词: Address; Antibodies; Arterial Fatty Streak; Atherosclerosis; Attenuated; Binding; Blood Circulation; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Culture Techniques; Cells; Cleaved cell; Complement; Complex; Consumption; Data; Deposition; Development; Drug Kinetics; Eating; Endothelial Cells; Endothelium; Enzymes; Excision; Excretory function; Food; Gastrointestinal tract structure; Genes; Glycoconjugates; Human; Immune; Incidence; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Injections; Intestines; Intravenous; Lead; Left; Lesion; Link; Mammals; Meat; Mediating; Metabolism; Mus; Necrosis; Neuraminidase; Oral; Pathway interactions; Peritoneal; Physiological; Polysaccharides; Prevention; Prevention strategy; Process; Reaction; Research; Risk; Role; Route; Sampling; Serum; Sialic Acids; Source; Structure; Testing; Therapeutic; Wild Type Mouse; Work; absorption; atherosclerosis risk; beef; cardiovascular risk factor; experimental study; feeding; gut bacteria; gut microbes; gut microbiome; gut microbiota; mouse model; novel; novel therapeutics; prevent; red meat consumption; subcutaneous; systemic inflammatory response; treatment strategy; uptake

Project Summary/Abstract One of the fundamental challenges facing cardiovascular research is the treatment of atherosclerosis, the single greatest cause of cardiovascular disease worldwide. Red meat consumption has long been linked to increased atherosclerosis incidence in humans, although not in other non-human mammals. A potential human-specific mechanism proposes that atherosclerosis is partly driven by an antibody-mediated reaction to the nonhuman sialic acid Neu5Gc, a molecule that is heavily enriched in red meat. Neu5Gc is structurally similar to the human sialic acid Neu5Ac, but humans cannot produce Neu5Gc due to an evolutionary loss of the CMAH enzyme gene. However, ingested Neu5Gc can be incorporated into the glycoconjugates of human cells, including endothelial cells. Cell culture and mouse models have shown that the presence of circulating anti-Neu5Gc antibodies leads to activation of endothelial inflammation pathways and increased atherosclerosis plaque size and necrotic core volume. Removal of Neu5Gc from endothelial glycoconjugates could therefore reduce activity of the inflammatory pathways that lead to atherosclerosis. This research seeks to use novel bacterial sialidases (enzymes that can cleave Neu5Gc) in a mouse model to reduce Neu5Gc uptake and incorporation into endothelial glycoconjugates, thereby mitigating atherosclerosis development. If successful, Neu5Gc sialidases would represent a new class of atherosclerosis treatment agents to pursue. Specifically, the aims of this proposal are to: (1) to enrich bacterial species producing Neu5Gc sialidases in gut microbiota, thereby reducing intestinal Neu5Gc uptake and preventing incorporation into endothelial glycoconjugates; and (2) to inject the sialidase Sia26 to therapeutically release Neu5Gc from endothelial glycoconjugates after it has been incorporated. A humanized (Cmah-/-) mouse model of atherosclerosis will be used to provide the physiological context critical for studying Neu5Gc-associated atherosclerosis risk. Together, these aims will address the effect of Neu5Gc sialidases on atherosclerosis through Neu5Gc cleavage in the gut and in circulation. The proposed studies will clarify the role of Neu5Gc as a human-specific trigger of atherosclerosis and investigate the potential of Neu5Gc sialidases as a novel treatment strategy.

项目总结/摘要 心血管研究面临的一个根本挑战是动脉粥样硬化的治疗， 心血管疾病的最大病因。长期以来，红肉消费一直与增加 在人类中动脉粥样硬化的发病率，虽然不是在其他非人类哺乳动物。一种潜在的人类特异性 一种机制提出动脉粥样硬化部分是由抗体介导的对非人类的反应驱动的。 唾液酸Neu 5Gc，一种在红肉中大量富集的分子。Neu 5Gc在结构上类似于人类 唾液酸Neu 5Ac，但由于CMAH酶基因的进化丢失，人类不能产生Neu 5Gc。 然而，摄入的Neu 5Gc可以掺入人细胞的糖缀合物中，包括内皮细胞。 细胞细胞培养和小鼠模型表明，循环抗Neu 5Gc抗体的存在导致 激活内皮炎症通路和增加动脉粥样硬化斑块大小和坏死核心 音量.因此，从内皮糖缀合物中去除Neu 5Gc可以降低内皮糖缀合物的活性。 导致动脉粥样硬化的炎症途径。 这项研究试图在小鼠模型中使用新型细菌唾液酸酶（可以切割Neu 5Gc的酶）， 减少Neu 5Gc摄取和掺入内皮糖缀合物，从而减轻动脉粥样硬化 发展如果成功，Neu 5Gc唾液酸酶将代表一类新的动脉粥样硬化治疗剂 去追求具体而言，本提案的目的是：（1）富集产生Neu 5Gc的细菌物种 肠道微生物群中的唾液酸酶，从而减少肠道Neu 5Gc的吸收并阻止其掺入 内皮糖缀合物;和（2）注射唾液酸酶Sia 26以治疗性地从内皮糖缀合物释放Neu 5Gc。 内皮糖缀合物后，它已被纳入。人源化（Cmah-/-）小鼠模型， 动脉粥样硬化将用于提供研究Neu 5Gc相关的生理背景， 动脉粥样硬化风险。总之，这些目标将解决Neu 5Gc唾液酸酶对动脉粥样硬化的影响 通过肠和循环中的Neu 5Gc裂解。拟议的研究将阐明Neu 5Gc作为 动脉粥样硬化的人类特异性触发因素，并研究Neu 5Gc唾液酸酶作为一种新型治疗方法的潜力 战略