Regulation of Antigen Presentation by APLP-2

APLP-2 对抗原呈递的调节

• 批准号: 6724993
• 负责人: Joyce C Solheim
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6724993
• 关键词: MHC class I antigen; SDS polyacrylamide gel electrophoresis; antigen presentation; antigen presenting cell; autoradiography; cellular immunity; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; immunoregulation; laboratory mouse; membrane proteins; peptides

DESCRIPTION (provided by applicant): The cellular immune response against infections is initiated at the level of peptide loading and assembly of major histocompatibility complex (MHC) class I molecules. MHC class I presentation of nonself peptides triggers killing of infected cells by cytolytic T lymphocytes. The assembly of the MHC class I heavy chain with antigenic peptide and beta2-microglobulin (Beta2m) occurs via association with endoplasmic reticulum (ER) proteins such as calnexin, TAP, calreticulin, tapasin, and ERp57. Another cellular protein, amyloid precursor-like protein 2 (APLP-2), has recently been shown to associate with MHC class I molecules, and our preliminary findings indicate that APLP-2 down regulates the quantity of MHC class I molecules at the cell surface. The long-range goal of our laboratory is to comprehend the regulation of antigen presentation by MHC class I molecules. The objective of this Exploratory/Developmental Research (R21) Grant proposal is to define the effect of APLP-2 on the presentation of pathogen-derived epitopes. Our central hypothesis is that APLP-2 regulates MHC class I maturation and presentation of pathogen-derived peptides, including known epitopes from NIAID biodefense priority pathogens (Hantaan virus, Mycobacterium tuberculosis, influenza A, dengue virus, Japanese encephalitis virus, and Listeria monocytogenes). New insights obtained from this study will clarify the role of APLP-2 in the regulation of the MHC class I assembly pathway and may lead to new immune-based means to prevent or treat infections. The Specific Aims of this proposal are: Aim 1. To ascertain the cellular location of interacting APLP-2/MHC class I molecules and the influence of APLP-2 on MHC class I presentation of peptide. We hypothesize that APLP-2 regulates MHC class l peptide presentation at a late stage in MHC class I maturation. Aim 2. To determine the effect of APLP-2 on T lymphocyte recognition of pathogen epitopes. We hypothesize that the presentation of epitopes from NIAID priority pathogens is affected by APLP-2 interaction with the MHC class I molecule.

描述(申请人提供)：针对感染的细胞免疫反应是在主要组织相容性复合体(MHC)I类分子的多肽负载和组装水平上启动的。MHC-I类非自体多肽可通过细胞溶解T淋巴细胞触发对感染细胞的杀伤作用。MHC-I类重链与抗原肽和β2-微球蛋白(Beta2m)的组装是通过与内质网(ER)蛋白如Calnexin、TAP、Calreticrin、Tapasin和ERp57结合而发生的。另一种细胞蛋白，淀粉样前体蛋白2(APLP-2)，最近被证明与MHC I类分子有关，我们的初步发现表明APLP-2下调了细胞表面MHC I类分子的数量。我们实验室的长期目标是了解MHC I类分子对抗原提呈的调节。这项探索性/发展性研究(R21)拨款提案的目的是确定APLP-2对病原体衍生表位呈现的影响。我们的中心假设是APLP-2调节MHC-I类病原体衍生多肽的成熟和呈递，包括NIAID生物防御优先病原体(汉滩病毒、结核分枝杆菌、甲型流感、登革病毒、日本脑炎病毒和单核细胞增生性李斯特菌)的已知表位。从这项研究中获得的新见解将阐明APLP-2在MHC I类组装途径调节中的作用，并可能导致基于免疫的新方法来预防或治疗感染。 本研究的具体目的是：1.确定APLP-2/MHC-I类分子相互作用的细胞位置以及APLP-2对MHC-I类递呈的影响。我们推测，在MHC-I类成熟的后期，APLP-2调节MHC-I类L多肽的提呈。目的2.探讨APLP-2对T淋巴细胞识别病原体表位的影响。我们假设NIAID优先病原体的抗原表位的呈现受到APLP-2与MHC I类分子相互作用的影响。