Peptide Repertoires of HLA class I molecules

HLA I 类分子的肽库

• 批准号: 9316821
• 负责人: MALINI RAGHAVAN
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316821
• 关键词: Address; Affinity; Antigen Presentation; Antigen Presentation Pathway; Antigens; Binding; Binding Sites; Bypass; CD8-Positive T-Lymphocytes; Cell Line; Cell surface; Cells; Communicable Diseases; Complex; Data Set; Detection; Disease; Disease Outcome; Endoplasmic Reticulum; Epitopes; Genes; Genetic Polymorphism; Genetic Variation; Genotype; HLA Antigens; Histocompatibility Antigens Class I; Human; Human Genetics; Immune response; Immunity; Infection; Infectious Agent; Inflammatory; Lead; MHC Class I Genes; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Methods; Outcome; Pathway interactions; Peptides; Predictive Factor; Process; Production; Proteins; Structure; Suggestion; T-Cell Receptor; Vaccine Design; Variant; Virus; antigen processing; antigenic peptide transporter; base; cancer cell; cytokine; liquid chromatography mass spectrometry; method development; novel; pathogen; peptide I; peptide structure; protein aminoacid sequence; tapasin

Major histocompatibility complex (MHC) class I molecules bind to peptide antigens and present these antigens to CD8 T cells. Human MHC class I variants are encoded by the HLA-A, HLA-B and HLA-C genes. These genes are highly polymorphic. The polymorphisms influence outcomes in a number of infectious diseases, cancers and inflammatory diseases. Among the three HLA class I loci, HLA-B molecules are shown have dominant influences upon outcomes in multiple diseases. A given HLA class I allotype can bind to a large number of cellular and pathogen-derived peptides, collectively called the peptidome. The diversity of HLA-B peptidomes could be one factor underlying their different effects upon disease outcomes. A number of factors are predicted to influence peptidome diversity among HLA class I allotypes, including the structure of the peptide-binding site, the intracellular assembly mechanism and the intrinsic stability of the peptide-deficient form. Several HLA-B molecules are assembled via unconventional intracellular pathways that are suggestive of the presence of novel unconventional epitopes within their peptidomes. We propose to use liquid chromatography mass spectrometry (LC-MS) methods to quantify, characterize and understand the full breadth of the peptidomes of selected HLA-B variants. Based on existing MS datasets, we will also develop globally normalized methods to quantify and compare peptidome diversities of different HLA-B variants. The findings of this study will be significant towards epitope and HLA selection during vaccine design against cancers and infectious diseases. The studies will also establish methods to identify novel disease-relevant epitopes, and allow a better understanding of the relationships between HLA class I genotypes and disease outcomes.

主要组织相容性复合物 (MHC) I 类分子与肽抗原结合并 将这些抗原呈递给 CD8 T 细胞。人类 MHC I 类变体由 HLA-A、HLA-B 和 HLA-C 基因。这些基因具有高度多态性。这 多态性影响许多传染病、癌症和 炎症性疾病。在三个 HLA I 类基因座中，显示了 HLA-B 分子 对多种疾病的结果具有显着影响。给定的 HLA I 类 同种异型可以结合大量细胞和病原体衍生的肽， 统称为肽组。 HLA-B 肽组的多样性可能是一个因素 揭示了它们对疾病结果的不同影响。有很多因素 预计会影响 HLA I 类同种异型之间的肽组多样性，包括 肽结合位点的结构、细胞内组装机制和 肽缺陷形式的内在稳定性。多个HLA-B分子被组装 通过非常规的细胞内途径，表明存在新的 其肽体内的非常规表位。我们建议使用液体 色谱质谱 (LC-MS) 方法用于定量、表征和 了解所选 HLA-B 变体的肽组的全部范围。基于 现有的 MS 数据集，我们还将开发全球标准化方法来量化和 比较不同 HLA-B 变体的肽组多样性。这项研究的结果将 在针对癌症的疫苗设计过程中对表位和 HLA 选择具有重要意义 和传染病。这些研究还将建立识别新颖的方法 疾病相关表位，并可以更好地理解之间的关系 HLA I 类基因型和疾病结果。