Regulation of Blood Glycoproteins by Lectin Receptors in Health and Disease

健康和疾病中凝集素受体对血液糖蛋白的调节

• 批准号: 10658456
• 负责人: JAMEY MARTH
• 金额: $ 48.75万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658456
• 关键词: Address; Aging; Alleles; Alpha-mannosidase; Animals; Autoimmune Diseases; Behavioral; Binding; Bioinformatics; Blood; Blood - brain barrier anatomy; Blood Coagulation Disorders; Blood Proteins; Blood Vessels; Blood brain barrier dysfunction; Blood specimen; Brain; Cardiovascular system; Cell surface; Cells; Chromatography; Chronic; Chronic Disease; Clinical; Collaborations; Data; Data Analyses; Defect; Degenerative Disorder; Development; Disease; Disease Marker; Distal; Environmental Risk Factor; Eukaryota; Exoglycosidases; Experimental Designs; Fucose; Functional disorder; Galactose; Glycoproteins; Glycoside Hydrolases; Golgi Apparatus; Health; Hematology; Human; Hydrolysis; Hypertension; Individual; Inflammation; Inflammatory; Innate Immune System; Investigation; Laboratories; Laboratory mice; Lectin; Lectin Receptors; Ligands; Link; Mammals; Mannose; Mannose Binding Lectin; Mannosidase; Mass Spectrum Analysis; Measures; Meta-Analysis; Molecular; Monitor; Mus; Neurologic; Onset of illness; Organ; Outcome; Pathologic; Pathology; Peptidyl-Dipeptidase A; Peroxidases; Phenotype; Physiological; Physiology; Plasma; Play; Polymers; Polysaccharides; Population; Predisposition; Process; Proteins; Proteome; Protocols documentation; Regulation; Renin; Research Proposals; Role; Sampling; Source; Sterility; Structure; Surface; Syndrome; System; Tissues; Vascular Diseases; anomer; autism spectrum disorder; blood pressure elevation; cell type; cohort; health determinants; inflammatory marker; inhibitor; link protein; mannose receptor; neural; pathogen; proteostasis; receptor binding; vascular inflammation

SUMMARY The composition of the blood proteome provides indications of normal health and the presence of disease. Over 90% of non-albumin proteins in the blood of mammals are N-glycoproteins bearing N-glycan structures produced in the Golgi apparatus prior to nascent glycoprotein secretion. We have previously discovered an intrinsic mechanism controlling the half-lives and thereby abundance and function of circulating blood glycoproteins. This mechanism is linked to the progressive glycosidic remodeling of nascent blood glycoproteins by circulating exo-glycosidases thereby resulting in the exposure of cryptic endocytic lectin receptor ligands. Endocytic lectin receptors are highly conserved among mammals and are expressed on the surface of various vascular and organ cell types where they recognize and bind their ligands from among circulating blood components and glycoproteins. We have found that this intrinsic mechanism of blood glycoprotein remodeling and clearance by lectin receptors is targeted by pathogens and the resulting changes in blood glycoprotein abundance are linked to disease onset. Lectin receptor ligands include glycosidic linkages of galactose, N-acetylglucosamine, fucose, or mannose; however, glycoproteins bearing physiological lectin receptor ligands remain mostly unknown and thus the functions of lectin receptors are also mysterious. This laboratory has developed an approach to identify physiological blood glycoprotein ligands of individual lectin receptors by chromatography and mass spectrometry protocols. A subset of mammalian lectin receptors bind to glycosidic linkages bearing exposed mannose, herein termed mannosylated blood glycoproteins. This laboratory discovered in past related studies that the accumulation of mannosylated glycoproteins due to defects in N-glycan synthesis causes chronic inflammation, autoimmunity, and degenerative disease. Normally however, the recognition and clearance of mannosylated blood glycoproteins involves the expression and function of mannose binding lectins including Mrc1. This proposal addresses the hypothesis that Mrc1 controls the levels of mannosylated blood glycoproteins in normal physiology and protects against the onset of disease. Our supporting data demonstrate that Mrc1 has a blood ligand repertoire including key regulators of the vasculature. Absence of Mrc1 results in the accumulation of mannosylated Renin and Angiotensin Converting Enzyme with elevated blood pressure. In addition, accumulating mannosylated Myeloperoxidase in the blood is associated with vascular inflammation, blood-brain barrier breakdown, tissue damage, and autism-like features. The roles of Mrc1 ligands will be addressed with inhibitors. In the blood of humans, we have further discovered a link between individuals with low levels of mannosidase activity and high levels of mannosylated blood proteins. This proposal in summary will investigate how the accumulation of mannosylated blood glycoprotein ligands in Mrc1 deficiency cause disease and establish whether humans bearing high levels of mannosylated blood glycoproteins similarly contain elevated markers of inflammation and vascular defects.

概括 血液蛋白质组的组成提供了正常健康状况和疾病存在的指示。 哺乳动物血液中超过 90% 的非白蛋白是带有 N-聚糖结构的 N-糖蛋白 在新生糖蛋白分泌之前在高尔基体中产生。我们之前发现了一个 控制半衰期从而控制循环血液的丰度和功能的内在机制 糖蛋白。这种机制与新生血液的渐进糖苷重塑有关 通过循环外切糖苷酶分解糖蛋白，从而导致隐藏的内吞凝集素的暴露 受体配体。内吞凝集素受体在哺乳动物中高度保守，并表达于 各种血管和器官细胞类型的表面，它们识别并结合其中的配体 循环血液成分和糖蛋白。我们发现血液的这种内在机制 凝集素受体的糖蛋白重塑和清除是病原体的目标，以及由此产生的变化 血液中糖蛋白的丰度与疾病的发生有关。凝集素受体配体包括糖苷 半乳糖、N-乙酰氨基葡萄糖、岩藻糖或甘露糖的键；然而，糖蛋白具有生理作用 凝集素受体配体大多仍是未知的，因此凝集素受体的功能也是神秘的。 该实验室开发了一种识别个体生理血糖蛋白配体的方法 通过色谱法和质谱法检测凝集素受体。哺乳动物凝集素受体的一个子集 结合带有暴露的甘露糖的糖苷键，本文称为甘露糖化血糖蛋白。这 实验室在过去的相关研究中发现，甘露糖蛋白的积累是由于 N-聚糖合成缺陷会导致慢性炎症、自身免疫和退行性疾病。通常情况下 然而，甘露糖化血糖蛋白的识别和清除涉及表达和 甘露糖结合凝集素（包括 Mrc1）的功能。该提案解决了 Mrc1 控制的假设 正常生理中甘露糖化血液糖蛋白的水平，并预防疾病的发作。 我们的支持数据表明 Mrc1 具有血液配体库，包括血液配体的关键调节因子 脉管系统。 Mrc1 的缺失会导致甘露糖化肾素和血管紧张素转换的积累 酶与血压升高。此外，血液中积累的甘露糖化髓过氧化物酶 与血管炎症、血脑屏障破坏、组织损伤和自闭症样症状有关 特征。 Mrc1 配体的作用将通过抑制剂来解决。在人类的血液中，我们还有 发现甘露糖苷酶活性水平低的个体与甘露糖苷化水平高的个体之间存在联系 血液蛋白质。总而言之，该提案将研究甘露糖化血液的积累如何 Mrc1 缺陷中的糖蛋白配体会导致疾病，并确定人类是否携带高水平的 甘露糖化血糖蛋白同样含有升高的炎症和血管缺陷标记物。