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Alliance of Glycobiologists for Detection of Cancer

癌症检测糖生物学家联盟

基本信息

批准号：
9142266
负责人：
RADOSLAV GOLDMAN
金额：
$ 50.53万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-14 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9142266
关键词：
Biological Assay Biological Markers Blood Circulation Cancer Detection Cirrhosis Detection Development Disease Disease Management Disease Outcome Fractionation Glycopeptides Glycoproteins Goals Gold Haptoglobins Health Human Human Genome Incidence Informatics Liver Liver Cirrhosis Liver diseases Malignant Neoplasms Malignant neoplasm of liver Methods Minor Modification Monitor Mutation N-Glycosylation Site Patients Peptides Polysaccharides Premalignant Prevention Research Primary carcinoma of the liver cells Protein Glycosylation Proteins Proteome Proteomics Reaction Research Resources SHBG gene Sampling Scheme Screening for Hepatocellular Cancer Screening for cancer Serological Serum Site Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staging United States Variant alpha-Fetoproteins base cancer biomarkers cancer prevention candidate marker carcinogenesis case control diagnostic accuracy glycoproteomics glycosylation improved mutant protein distribution repository validation studies

项目摘要

DESCRIPTION (provided by applicant): This proposal aims to detect hepatocellular carcinoma (HCC) at a treatable stage by non-invasive methods. To this end, we propose to quantify site specific glycoforms of liver secreted N-glycoproteins (LNP) associated with the progression of liver disease to HCC. We and others have shown that changes in protein glycosylation accompany the development of HCC. Major re-distribution of protein N-glycoforms occurs at the premalignant stage of liver cirrhosis but our latest studies show that specific glycoforms of a glycopeptide of haptoglobin increase exclusively in HCC. We demonstrate that these minor glycoforms of haptoglobin are detectable in serum and have the potential to improve detection of HCC compared to the serologic gold standard, alpha fetoprotein (AFP). This supports our hypothesis that minor site specific glycoforms of abundant liver secreted N-glycoproteins provide HCC specific marker candidates detectable in the circulation. We propose to complete identification of the HCC specific N-glycans; we have already evidence that the glycans are characterized by multiple fucosylations and increased branching. We propose to identify glycopeptides of additional proteins carrying these HCC specific N-glycan modifications by newly optimized mass spectrometric methods. This is done because haptoglobin is downregulated in a fraction of cirrhotics and other proteins may be needed for optimal detection. We expand our informatic analysis to classify all polymorphic and mutant human N- glycoproteins with newly created or abolished N-glycosylation sites. These protein variants are over- represented in the human genome, represent prime candidates for association with diseases, and we expect that they have direct impact on carcinogenesis. We believe that a publically available resource of these variant proteins will stimulate glycoproteomic cancer prevention research. The proposed examination of HCC specific N-glycoforms is feasible because we have already created a repository of samples of HCC patients and cirrhotic controls. This repository, and additional outstanding QC resources, is essential for the isolation of the HCC specific minor glycoforms of liver secreted N-glycoproteins; these glycoforms are not detectable in disease free subjects. By the end of the study, we will have quantified the selected site specific protein glycoforms by targeted LC-MS selective reaction monitoring (SRM) methods. These methods will quantify the HCC associated site specific glycopeptides in serum with an unprecedented accuracy. We do this because we believe that quantification of specific glycoforms of specific glycoprotein peptides offers the highest diagnostic accuracy. Defining clinically applicable cancer markers has potentially far-reaching consequences for disease management and patient health. Our study is expected to generate new hypotheses on the functional impact of protein glycosylation on the development of cancer and to stimulate an entirely new line of cancer prevention and detection research.

描述（由申请人提供）：该提案旨在通过非侵入性方法检测可治疗阶段的肝细胞癌（HCC）。为此，我们建议量化与肝病进展为 HCC 相关的肝脏分泌 N 糖蛋白 (LNP) 的位点特异性糖型。我们和其他人已经证明蛋白质糖基化的变化伴随着 HCC 的发展。蛋白质 N-糖型的主要重新分布发生在肝硬化的癌前阶段，但我们的最新研究表明，触珠蛋白糖肽的特定糖型仅在 HCC 中增加。我们证明，触珠蛋白的这些次要糖型可以在血清中检测到，并且与血清学金标准甲胎蛋白 (AFP) 相比，有可能改善 HCC 的检测。这支持了我们的假设，即丰富的肝脏分泌的 N-糖蛋白的次要位点特异性糖型提供了循环中可检测到的 HCC 特异性候选标记物。我们建议完成 HCC 特异性 N-聚糖的鉴定；我们已经有证据表明聚糖的特征是多重岩藻糖基化和增加的分支。我们建议通过新优化的质谱方法来鉴定携带这些 HCC 特异性 N-聚糖修饰的其他蛋白质的糖肽。这样做是因为触珠蛋白在部分肝硬化患者中下调，并且可能需要其他蛋白质才能实现最佳检测。我们扩展了信息分析，以对具有新创建或废除的 N-糖基化位点的所有多态性和突变型人类 N-糖蛋白进行分类。这些蛋白质变体在人类基因组中大量存在，是与疾病相关的主要候选者，我们预计它们对致癌作用有直接影响。我们相信，这些变异蛋白的公开资源将刺激糖蛋白组癌症预防研究。拟议的 HCC 特异性 N-糖型检查是可行的，因为我们已经创建了 HCC 患者和肝硬化对照样本的存储库。该存储库以及其他出色的 QC 资源对于分离肝脏分泌的 N-糖蛋白的 HCC 特定次要糖型至关重要；在无病受试者中检测不到这些糖型。在研究结束时，我们将通过有针对性的 LC-MS 选择性反应监测 (SRM) 方法对选定的位点特异性蛋白质糖型进行量化。这些方法将以前所未有的准确性量化血清中与 HCC 相关的位点特异性糖肽。我们这样做是因为我们相信特定糖蛋白肽的特定糖型的定量可提供最高的诊断准确性。定义临床适用的癌症标志物对疾病管理和患者健康具有潜在的深远影响。我们的研究预计将产生关于蛋白质糖基化对癌症发展的功能影响的新假设，并激发全新的癌症预防和检测研究。