PEPTIDES IDENTIFIED FROM THE TYPE I DIABETES ASSOCIATED MHC CLASS I-H2-KD

从 I 型糖尿病相关 MHC I-H2-KD 类中鉴定出的肽

• 批准号: 7953898
• 负责人: EMIL Raphael UNANUE
• 金额: $ 0.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953898
• 关键词: Address; Affinity; Amino Acids; Area; Autoantigens; Autoimmune Diabetes; Binding; Biological; Cancer Vaccines; Complex; Computer Retrieval of Information on Scientific Projects Database; Disease; Dissociation; Epitopes; Funding; Grant; Histocompatibility Antigens Class II; Immune response; Institution; Insulin-Dependent Diabetes Mellitus; Investigation; Length; Life; Major Histocompatibility Complex; Mass Spectrum Analysis; Nature; Outcome; Peptides; Play; Process; Research; Research Personnel; Resources; Role; Source; Specificity; Synthetic Peptide Libraries; United States National Institutes of Health; Viral; base; biomedical resource; improved; pathogen; research study; response; tumor immunology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The repertoire of peptides bound by major histocompatability complexes (MHC) determines the fate of important biological outcomes such as the cellular defense and immune responses to foreign invaders or in some aberrant cases reactivity to self antigens. Detailed analyses of naturally processed peptides from class I and II MHC molecules have revealed certain general features, for example the lengths of naturally processed peptides selected by class I MHC molecules are usually restricted to 8-10-mers whereas those selected by class II MHC molecules are longer and more variable, usually between 14-24-mer. More importantly, detailed analyses of naturally processed peptides have addressed key issues regarding the specificity of peptide-selection among closely related MHC molecules, which was not evident in prior studies involving synthetic peptide libraries. In this analyses, we sought to identify the nature and motif of peptides that are selected by the class I MHC molecule, H-2Kd. We selected H-2Kd because it may play a significant role in several areas of disease including: responses against viral and bacterial pathogens, autoimmune diabetes, tumor immunology, and the efficacy of peptide-based tumor vaccines. Results from our analyses of large numbers of peptides selected by H-2Kd have firmly established the peptide-binding motif. Although a large fraction of naturally selected peptides were 8 to 10 amino acids in length, there were a significant fraction that were of longer length, some as long as 18-mers. Binding studies demonstrated that while the short peptides bound with higher affinity and formed long-lived peptide-MHC complexes, the longer peptides bound weakly and had a fast dissociation rate. Trimming the long peptides did not improve binding interactions and conversely extending the 9-mer naturally processed epitopes did not decrease binding. Finally, the mode of binding of the longer peptides was investigated. Results from these experiments demonstrate that the Naturally processed peptides selected by H-2Kd varied in length from 8-mers to 18-mers ? although most peptides were 8-10 amino acids, there was a significant fraction that were 10 amino acids in length. The immunological significance of these peptides is currently under investigation.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 主要组织相容性复合物 (MHC) 结合的肽库决定了重要生物学结果的命运，例如对外来入侵者的细胞防御和免疫反应，或在某些异常情况下对自身抗原的反应性。 对来自 I 类和 II 类 MHC 分子的天然加工肽的详细分析揭示了某些一般特征，例如由 I 类 MHC 分子选择的天然加工肽的长度通常限于 8-10 聚体，而由 II 类 MHC 分子选择的长度更长且变化更大，通常在 14-24 聚体之间。 更重要的是，对天然加工肽的详细分析解决了密切相关的 MHC 分子中肽选择特异性的关键问题，这在涉及合成肽库的先前研究中并不明显。 在本次分析中，我们试图鉴定由 I 类 MHC 分子 H-2Kd 选择的肽的性质和基序。我们选择 H-2Kd 是因为它可能在多个疾病领域发挥重要作用，包括：针对病毒和细菌病原体的反应、自身免疫性糖尿病、肿瘤免疫学以及基于肽的肿瘤疫苗的功效。 我们对 H-2Kd 选择的大量肽的分析结果已经牢固地确立了肽结合基序。尽管大部分自然选择的肽长度为 8 至 10 个氨基酸，但也有相当一部分长度更长，有些长达 18 聚体。 结合研究表明，虽然短肽以较高的亲和力结合并形成长寿命的肽-MHC 复合物，但较长的肽结合较弱且解离速率较快。修剪长肽并不会改善结合相互作用，相反，延长 9 聚体自然加工的表位也不会减少结合。最后，研究了较长肽的结合模式。这些实验的结果表明，H-2Kd 选择的自然加工肽的长度从 8 聚体到 18 聚体不等？尽管大多数肽由 8-10 个氨基酸组成，但也有相当一部分肽的长度为 10 个氨基酸。 这些肽的免疫学意义目前正在研究中。