Peptide Repertoires of HLA class I molecules

HLA I 类分子的肽库

基本信息

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
项目类别：
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

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

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项目摘要

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.

主要的组织相容性复合物（MHC）I类分子与肽抗原和将这些抗原呈现给CD8 T细胞。人类MHC I类变体由 HLA-A，HLA-B和HLA-C基因。这些基因是高度多态的。这多态性会影响多种传染病，癌症和炎症性疾病。在三个HLA I类位点中，显示了HLA-B分子对多种疾病的结局有主要影响。给定的HLA I类同种型可以与大量细胞和病原体衍生的肽结合，统称为肽组。 HLA-B肽组的多样性可能是一个因素它们对疾病结局的影响不同。许多因素是预计会影响HLA I类同型的肽组多样性，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。组装了几个HLA-B分子通过非常规的细胞内途径，暗示存在新型其肽组中的非常规表位。我们建议使用液体色谱质谱法（LC-MS）方法来量化，表征和了解选定的HLA-B变体肽组的完整宽度。基于现有的MS数据集，我们还将开发全球标准化的方法来量化和比较不同HLA-B变体的肽组多样性。这项研究的发现将疫苗设计期间对癌症的表位和HLA选择意义和传染病。研究还将建立识别新颖的方法与疾病相关的表位，并可以更好地理解 HLA I类基因型和疾病结果。