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和疾病存在的迹象。 哺乳动物血液中超过90％的非α蛋白蛋白是N-糖蛋白N-糖蛋白具有N-聚糖结构 在新生糖蛋白分泌之前在高尔基体中产生。我们以前已经发现了 控制半衰期的固有机制，从而丰富和功能循环血液 糖蛋白。该机制与新生血液的进行性糖苷重塑有关 通过循环外糖苷酶循环糖蛋白，从而导致隐性内吞凝集素的暴露 受体配体。内吞凝集素受体在哺乳动物中高度保守，并在 各种血管和器官细胞类型的表面，它们识别并结合其配体的表面 循环的血液成分和糖蛋白。我们发现这种血液的内在机制 凝集素受体的糖蛋白重塑和清除率是病原体的靶向和结果的变化 在血液糖蛋白中，丰度与疾病发作有关。凝集素受体配体包括糖苷 半乳糖，N-乙酰葡萄糖，岩藻糖或甘露糖的连接；但是，具有生理的糖蛋白 凝集素受体配体主要未知，因此凝集素受体的功能也很神秘。 该实验室已经开发了一种方法来鉴定个体的生理血液糖蛋白配体 通过色谱和质谱法方案通过凝集素受体。哺乳动物凝集素受体的子集 与含有暴露甘露糖的糖苷键结合，在此称为甘露糖基化的血糖蛋白。这 实验室在过去的相关研究中发现，由于 N-聚糖合成的缺陷会导致慢性炎症，自身免疫性和退化性疾病。通常情况下 然而，甘露糖基化血液糖蛋白的识别和清除涉及表达和 包括MRC1在内的甘露糖结合凝集素的功能。该提案解决了MRC1控制的假设 正常生理学中的甘露糖基化血糖蛋白水平，可预防疾病的发作。 我们的支持数据表明，MRC1具有血配体曲目，包括 脉管系统。缺乏MRC1会导致甘露糖基化肾素和血管紧张素转化的积累 血压升高的酶。另外，血液中累积甘露糖基化的髓过氧化物酶是 与血管炎症，血脑屏障分解，组织损伤和自闭症一样 特征。 MRC1配体的作用将与抑制剂有关。在人类的血中，我们还有进一步 发现甘露糖苷酶活性低的个体与高水平的甘露糖基化之间的联系 血蛋白。总而言之，该提案将研究甘露糖基化血液的积累 MRC1缺乏症中的糖蛋白配体引起疾病，并确定人类是否具有高水平的人 甘露糖基化的血糖蛋白类似地含有炎症和血管缺陷的升高。