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.

总结 血液蛋白质组的组成提供了正常健康和疾病存在的指示。 哺乳动物血液中90%以上的非白蛋白是具有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 控制半衰期的内在机制，从而控制循环血液的丰度和功能 糖蛋白这一机制与新生血液的进行性糖苷重塑有关 通过循环外切糖苷酶，从而导致隐藏的内吞凝集素暴露， 受体配体内吞凝集素受体在哺乳动物中是高度保守的，并且在哺乳动物的细胞膜上表达。 各种血管和器官细胞类型的表面，在那里它们识别并结合来自 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靶向， 在血液中糖蛋白丰度与疾病发作有关。凝集素受体配体包括糖苷配体。 半乳糖、N-乙酰葡糖胺、岩藻糖或甘露糖的键;然而，具有生理活性的糖蛋白 凝集素受体配体仍然是未知的，因此凝集素受体的功能也是神秘的。 本实验室开发了一种鉴定个体生理性血液糖蛋白配体的方法， 通过色谱和质谱方案测定凝集素受体。哺乳动物凝集素受体的亚类 与带有暴露的甘露糖的糖苷键结合，在此称为甘露糖基化血糖蛋白。这 实验室在过去的相关研究中发现，甘露糖基化糖蛋白的积累是由于 N-聚糖合成的缺陷引起慢性炎症、自身免疫和变性疾病。通常 然而，甘露糖基化血液糖蛋白的识别和清除涉及表达， 甘露糖结合凝集素包括Mrc 1的功能。该提议解决了Mrc 1控制 甘露糖基化的血液糖蛋白的水平在正常的生理和防止疾病的发作。 我们的支持性数据表明，Mrc 1具有血液配体库，包括血液配体的关键调节因子。 脉管系统Mrc 1的缺失导致甘露糖基化的肾素和血管紧张素转化酶的积累 会导致血压升高的酶。此外，在血液中积累甘露糖基化髓过氧化物酶， 与血管炎症、血脑屏障破坏、组织损伤和自闭症样 功能. Mrc 1配体的作用将与抑制剂一起解决。在人类的血液中， 发现了低水平甘露糖苷酶活性和高水平甘露糖基化之间的联系。 血蛋白本提案总结将调查如何积累甘露糖化的血液 Mrc 1缺乏症中的糖蛋白配体引起疾病，并确定是否携带高水平的 甘露糖基化的血糖蛋白类似地含有升高的炎症和血管缺陷的标志物。