ER Proteins Effect on Class I MHC Assembly

ER 蛋白对 I 类 MHC 组装的影响

基本信息

批准号：
7922974
负责人：
Joyce C Solheim
金额：
$ 8.96万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7922974
关键词：
Academic Medical Centers Affinity Antigen Presentation Area Arthritis Autoimmune Diseases Autoimmunity Binding Biochemical Biochemistry Cell physiology Cell surface Cells Clinical Cancer Center Collaborations Complex Cytolysis Cytotoxic T-Lymphocytes Development Diabetes Mellitus Disease ERp57 Endoplasmic Reticulum Funding Goals Graft Rejection Grant Head Immune response Immunologist Immunotherapeutic agent In Vitro Infection Infectious Agent Institutes Ligands Major Histocompatibility Complex Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Molecular Natural Killer Cells Nebraska Neoplasm Transplantation Peptides Play Principal Investigator Proteins Recruitment Activity Regulation Research Research Institute Role Scientist Site Speed Surface System T-Lymphocyte Technical Expertise Technology Therapeutic Thymus Gland Universities Virginia Virus antigenic peptide transporter authority calreticulin cytotoxic defined contribution expectation improved in vivo innovation mutant pathogen peptide I programs protein complex response tapasin therapy development transplantation medicine tumor vaccine development

项目摘要

DESCRIPTION (provided by applicant): MHC presentation of peptide has broad importance, as shown by the range of disease conditions influenced by MHC molecules, e.g. infections, tumors, transplantation rejection, and autoimmunity. Cell surface major histocompatibility complex (MHC) class I molecules present tumor- or pathogen-specific peptides to T cells, which respond by lysing malignant or infected cells. Self-MHC class I/peptide complexes are required for the primary selection of the host's repertoire of cytolytic T lymphocytes. In addition, the number of surface MHC class I molecules on target cells influences their recognition by natural killer cells. For all these reasons, cell surface expression of peptide-bearing MHC class I molecules is of immunological importance. Before egress to the cell surface, MHC class I molecules receive peptides within a complex of proteins in the endoplasmic reticulum. In the peptide-loading complex, the protein calreticulin binds to the MHC class I heavy chain, and its presence in the complex is up-regulated by tapasin. Tapasin binds to the MHC class I heavy chain, recruits ERp57 and the transporter associated with antigen processing (TAP), and stabilizes TAP. Although tapasin serves as a critical factor in the control of MHC class I surface expression and peptide presentation, the mechanisms whereby it regulates MHC class I assembly are poorly understood. A more complete understanding of the importance of MHC class I peptide-loading complex interactions involving tapasin would contribute to the creation of strategies to influence peptide presentation for many therapeutic purposes. The objective of this project is to define the mechanisms by which antigen presentation by MHC class I molecules is regulated. Our central hypothesis is that specific interactions of tapasin with other assembly complex proteins regulate the sequence and affinity of MHC class I-binding peptides, the stability of MHC class I/p2m heterodimers prior to final peptide binding, and ultimately cytotoxic T lymphocyte selection and response. We propose these Aims: 1) to determine the role of peptide-loading complex interactions in the stabilization of complete MHC molecules and in the regulation of the MHC class I peptide repertoire, 2) to define the effect of assembly complex interactions on the stability of open MHC class I/p2m heterodimers, and 3) to characterize the impact of peptide-loading complex interactions on T cell recognition, response, and development, using in vitro and in vivo systems. At the completion of this project, it is our expectation that we will have defined contributions of the peptide-loading complex involving tapasin to the regulation of the MHC class I-binding peptide repertoire, MHC class I stabilization, and T cell function.

描述（由申请人提供）：肽的 MHC 呈递具有广泛的重要性，如受 MHC 分子影响的一系列疾病所示，例如，感染、肿瘤、移植排斥和自身免疫。细胞表面主要组织相容性复合物 (MHC) I 类分子将肿瘤或病原体特异性肽呈递给 T 细胞，T 细胞通过裂解恶性或受感染的细胞做出反应。自身 MHC I 类/肽复合物是宿主溶细胞 T 淋巴细胞库的初步选择所必需的。此外，靶细胞表面MHC I类分子的数量也会影响自然杀伤细胞对它们的识别。由于所有这些原因，带有肽的 MHC I 类分子的细胞表面表达具有免疫学重要性。在流出到细胞表面之前，MHC I 类分子在内质网中的蛋白质复合物中接收肽。在肽负载复合物中，蛋白质钙网蛋白与 MHC I 类重链结合，并且其在复合物中的存在被 tapasin 上调。 Tapasin 与 MHC I 类重链结合，招募 ERp57 和与抗原加工 (TAP) 相关的转运蛋白，并稳定 TAP。尽管 Tapasin 是控制 MHC I 类表面表达和肽呈递的关键因素，但其调节 MHC I 类组装的机制却知之甚少。更全面地了解涉及塔帕辛的 MHC I 类肽负载复合物相互作用的重要性将有助于制定影响肽呈递以用于许多治疗目的的策略。该项目的目的是确定 MHC I 类分子抗原呈递的调节机制。我们的中心假设是，tapasin 与其他组装复合物蛋白的特异性相互作用调节 MHC I 类结合肽的序列和亲和力、MHC I 类/p2m 异二聚体在最终肽结合之前的稳定性，并最终调节细胞毒性 T 淋巴细胞的选择和反应。我们提出以下目标：1) 确定肽负载复合物相互作用在完整 MHC 分子的稳定和 MHC I 类肽库的调节中的作用，2) 确定组装复合物相互作用对 MHC 分子稳定性的影响开放 MHC I 类/p2m 异二聚体，3) 使用体外和体内系统表征肽负载复合物相互作用对 T 细胞识别、反应和发育的影响。在该项目完成时，我们期望我们能够确定涉及 tapasin 的肽负载复合物对 MHC I 类结合肽库、MHC I 类稳定性和 T 细胞功能的调节的贡献。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Analysis of major histocompatibility complex class I interactions with endoplasmic reticulum proteins.

DOI：
10.1385/1-59259-062-4:165
发表时间：
2001
期刊：
Methods in molecular biology
影响因子：
0
作者：
H. Turnquist;J. Solheim
通讯作者：
H. Turnquist;J. Solheim

Effect of linkage of transduction domain sequences to a lymphoma idiotype DNA vaccine on vaccine effectiveness.

转导结构域序列与淋巴瘤独特型 DNA 疫苗的连接对疫苗有效性的影响。

DOI：
10.1089/hyb.2006.25.306
发表时间：
2006
期刊：
Hybridoma (2005)
影响因子：
0
作者：
Ashour,Abdel-Kader;Petersen,JasonL;McIlhaney,MaryM;Vose,JulieM;Solheim,JoyceC
通讯作者：
Solheim,JoyceC

Specificity of amyloid precursor-like protein 2 interactions with MHC class I molecules.

淀粉样前体样蛋白 2 与 MHC I 类分子相互作用的特异性。