Sialoglycoproteomic network and target discovery for Alzheimer's disease

唾液酸糖蛋白质组网络和阿尔茨海默病的靶标发现

• 批准号: 10734612
• 负责人: LIAN LI
• 金额: $ 78.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734612
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease diagnostic; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Animal Model; Area; Autopsy; Binding; Biological; Biological Markers; Biology; Blood; Brain; Carbon; Cell surface; Cellular biology; Cerebrospinal Fluid; Charge; Clinical; Couples; DNA Sequence Alteration; Data; Dementia; Development; Disease; Disease Progression; Drug Targeting; Early Diagnosis; Early Intervention; Enzymes; Functional disorder; Glycoproteins; Health; Homeostasis; Human; Immunoglobulins; Intervention; Knowledge; Lectin; Link; Masks; Mass Spectrum Analysis; Mediating; Metabolism; Molecular; Molecular Target; Monitor; Monosaccharides; Mutation; NRCAM gene; Neuraminic Acids; Neuraminidase; Neurodegenerative Disorders; Neurologic; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Post-Translational Protein Processing; Prevention; Process; Protein Conformation; Proteins; Research; Resolution; Risk Factors; Role; Sampling; Serum; Sialic Acids; Sialoglycoproteins; Sialyltransferases; Signal Transduction; Site; Source; Specimen; Study models; System; Systems Biology; Testing; Translational Research; Validation; biomarker development; biomarker discovery; brain dysfunction; brain tissue; case control; disease prognosis; effective therapy; extracellular; follow-up; genome wide association study; glycoproteomics; human disease; improved; in vivo; innovation; insight; mild cognitive impairment; molecular recognition; neuropathology; novel; novel marker; protein folding; sialic acid binding Ig-like lectin; sialylation; targeted treatment; therapeutic development; trafficking

Project Summary / Abstract Alzheimer's disease (AD) is a devastating dementia with no effective treatment, underscoring the critical need for better understanding the pathogenic mechanisms of this disease and uncovering new molecular vulnerabilities to target for therapy. This project addresses an important yet under-studied area of AD research and aims to discover sialylation-mediated disease processes and novel targets for early diagnosis and intervention. Protein sialylation is a post-translational modification that covalently attaches sialic acids (negatively charged nine-carbon monosaccharides also known as neuraminic acids) onto glycoproteins to generate sialoglycoproteins. Accumulating evidence indicates that sialic acids on sialoglycoproteins not only affect protein conformation, activity, and trafficking, but also serve as regulators of molecular and cellular interactions, acting as a biological mask for blocking molecular recognition and/or as a biological recognition signal for mediating interactions with specific proteins such as Siglecs (sialic-acid-binding immunoglobulin- type lectins). Protein sialylation is vital to brain function and homeostasis, as highlighted by the fact that genetic mutations in enzymes for catalyzing sialylation, desialylation, or sialic acid metabolism cause human diseases with brain dysfunction and neurological abnormalities. Furthermore, GWAS studies have identified Siglec-3 (also known as CD33) as a risk factor for AD, underlining the connection between dysregulated sialylation-mediated signaling and AD pathogenesis. However, very little is currently known about human brain sialoglycoproteome and its alterations in AD. The proposed project will address this knowledge gap and use an innovative, multi-faceted approach that combines sialoglycoproteomics, network biology, cell biology with translational research in human patient specimens to discover and study sialoglycoproteomic networks and sialylation-based molecular mechanisms and pathways underlying brain function in health and Alzheimer's disease. Furthermore, this project will perform large-scale high-resolution analyses of sialoglycoproteome changes in human AD and control cerebrospinal fluid, and blood serum samples to identify novel biomarkers for early diagnosis and monitoring disease progression. Findings from the proposed research will advance our understanding of AD pathogenesis and provide novel targets for AD diagnostic and therapeutic development.

项目摘要 /摘要 阿尔茨海默氏病（AD）是一种毁灭性的痴呆，没有有效的治疗，强调了关键 需要更好地了解该疾病的致病机制并揭示新的分子 靶向治疗的脆弱性。该项目解决了广告的重要但研究不足的领域 研究和旨在发现溶解介导的疾病过程和早期诊断的新目标 和干预。蛋白质溶解度是一种翻译后的修饰，可连接唾液酸 （带负电荷的九碳单糖也称为神经氨酸）到糖蛋白上 产生唾液糖蛋白。积累的证据表明唾液糖蛋白上的唾液酸不仅 影响蛋白质构象，活性和运输，但也可以作为分子和细胞的调节剂 相互作用，充当用于阻断分子识别和/或生物学识别的生物学面膜 信号用于介导与特定蛋白（例如Siglecs）（唾液酸结合免疫球蛋白）相互作用的信号 类型凝集素）。蛋白质溶解对脑功能和稳态至关重要，这是这样强调的 酶的遗传突变，用于催化溶酶，脱酰化或唾液酸代谢引起人类 脑功能障碍和神经系统异常的疾病。此外，GWAS研究已经确定 SIGLEC-3（也称为CD33）是AD的危险因素，强调了失调的连接 囊酰化介导的信号传导和AD发病机理。但是，目前对人类知之甚少 大脑唾液糖蛋白酶及其在AD中的改变。拟议的项目将解决这个知识差距 并使用一种创新的，多方面的方法，结合了唾液酸蛋白质组学，网络生物学，细胞 生物学与人类患者标本中的转化研究一起发现和研究唾液酸糖蛋白质组学 网络和基于溶解度的分子机制和途径在健康和 阿尔茨海默氏病。此外，该项目将进行大规模的高分辨率分析 人AD和控制脑脊液的唾液糖蛋白酶变化，血清样品 确定新型生物标志物，以早期诊断和监测疾病进展。提议的发现 研究将提高我们对AD发病机理的理解，并为AD诊断提供新的目标 和治疗发展。