Carboxypeptidase ACE and MHC Class I Presentation

羧肽酶 ACE 和 MHC I 类介绍

• 批准号: 8969984
• 负责人: KENNETH E BERNSTEIN
• 金额: $ 21.82万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969984
• 关键词: Affect; Amino Acids; Aminopeptidase; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Applications Grants; Autologous; Biochemical; CD8B1 gene; Carboxypeptidase; Cells; Cleaved cell; Data; Dipeptidases; Endoplasmic Reticulum; Enzyme Inhibition; Epitopes; Genes; Goals; Grant; Histocompatibility Antigens Class I; Immune response; Immunologics; Immunology; Infection; Knockout Mice; Length; Major Histocompatibility Complex; Mediating; Mus; Mutate; Nature; Pathway interactions; Patients; Peptide Hydrolases; Peptide Mapping; Peptides; Peptidyl-Dipeptidase A; Physiological; Process; Proteins; Publishing; Reporting; Role; Scientist; Shapes; Specificity; Substrate Specificity; Surface; T cell response; T-Lymphocyte; Vasoconstrictor Agents; Viral Antigens; Virus; Virus Diseases; Wild Type Mouse; Work; Zinc; adaptive immunity; amyloid peptide; antigen processing; base; blood pressure regulation; immunogenic; insight; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutics; pathogen; peptide I; public health relevance; tumor; vaccination strategy

 DESCRIPTION (provided by applicant): The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell mediated protection from tumor and viral infection. A major goal of scientists studying adaptive immunity is to understand precisely how a cell generates it's unique immunogenic "peptide fingerprint". This proposal is based on our novel finding that angiotensin converting enzyme (ACE) is the major carboxypeptidase editing the C-termini of MHC class I peptides. Preliminary data show that ACE knockout mice present a distinctive class I peptide repertoire which contains novel antigens not present on wild-type mice. In addition, ACE expression is increased with the maturation of antigen presenting cells and also induced by infection. These data imply an important physiologic role for ACE during immunologic challenge, including the CD8+ T cell responses to viral infection. The overarching goal of the present proposal is to develop a deeper biochemical and physiological understanding of the involvement of the carboxypeptidase ACE in MHC class I antigen processing. Given the large number of patients taking ACE inhibitors, this is an important goal. Specifically, I propose (Aim I) to study the specificity of ACE in producing MHC class I peptides. This aim will examine the biochemical specificity of ACE and a possible synergy effect of ACE and proteasome in producing MHC class I peptides. Moreover, the effect of ACE inhibitor in changing MHC class I antigen presentation will be evaluated. I also propose (Aim II) to investigate the physiological roles of ACE in antigen processing and immune responses to viral infection. Here, I will evaluate viral antigen presentation and virus progressio in animals expressing different levels of ACE. In particular, I will determine whether ACE impacts the virus-derived immunodominance. The completion of both aims will not only broaden our understating of antigen presentation, but may provide novel targets and strategies to boost adaptive immunity against pathogenic infection and tumors.

 描述（由适用提供）：通过主要的组织相容性复合物（MHC）I类分子对Petides的表面表现对于CD8+ T细胞介导的肿瘤和病毒感染的保护至关重要。研究适应性免疫史的科学家的一个主要目标是精确地了解细胞如何产生其独特的免疫原性“肽指纹”。该建议基于我们的新发现，即血管紧张素转化酶（ACE）是编辑MHC I类肽的C末端的主要羧肽酶。初步数据表明，ACE敲除小鼠具有独特的I类肽库，该肽库中包含不存在野生型小鼠上的新型抗原。另外，随着抗原呈递细胞的成熟，ACE表达增加，也通过感染诱导。这些数据意味着在免疫学挑战中ACE的重要生理作用，包括CD8+ T细胞对病毒感染的反应。本提案的总体目标是对羧肽酶ACE参与MHC I类抗原处理的参与产生更深入的生化和物理理解。考虑到大量服用ACE抑制剂的患者，这是一个重要目标。具体来说，我建议（目标I）研究ACE在生产MHC I类Pepperides中的特殊性。该目标将检查ACE的生化特异性以及ACE和蛋白酶体在生产MHC I类肽中的可能协同作用。此外，将评估ACE抑制剂在更改MHC I类抗原表现中的影响。我还建议（AIM II）研究ACE在抗原加工中的身体作用，并对病毒感染的免疫回应。在这里，我将评估表达不同ACE水平的动物中的病毒抗原表现和病毒进度。特别是，我将确定ACE是否会影响病毒衍生的免疫主持。两种目标的完成不仅将扩大我们对抗原表现的理解，而且可以提供新的目标和策略，以增强针对致病感染和肿瘤的适应性免疫学。