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）：MHC的肽表现具有广泛的重要性，如受MHC分子影响的疾病范围所示，例如感染，肿瘤，移植排斥和自身免疫性。细胞表面主要的组织相容性复合物（MHC）I类分子向T细胞呈现肿瘤或病原体特异性肽，这些肽是通过裂解恶性或感染细胞反应的。自我MHC I/肽复合物是宿主胞质T淋巴细胞曲目的主要选择所必需的。另外，靶细胞上的表面MHC I类分子的数量会影响自然杀伤细胞的识别。由于所有这些原因，含有肽的MHC I类分子的细胞表面表达具有免疫学重要性。在出口到细胞表面之前，MHC I类分子在内质网中的蛋白质复合物中接受肽。在肽加载络合物中，蛋白钙网蛋白与MHC I类重链结合，其在复合物中的存在被木薯素上调。小吃结合了MHC I类重链，招募ERP57和与抗原加工（TAP）相关的转运蛋白，并稳定TAP。尽管小吃是控制MHC I类表面表达和肽表现的关键因素，但调节MHC I类组装的机制知之甚少。对MHC I类肽的重要性的重要性更完整地理解涉及木薯素的复杂相互作用将有助于创建影响许多治疗目的的肽表现的策略。该项目的目的是定义MHC I类分子的抗原表现的机制。我们的中心假设是，木薯素与其他组装复合蛋白的特定相互作用调节MHC I类结合肽的序列和亲和力，MHC类I/P2M类异二聚体在最终肽结合之前的稳定性，以及最终最终导致细胞毒性T淋巴细胞的选择和反应。 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开发，使用体外和体内系统。该项目完成后，我们期望我们将定义涉及木薯素对MHC I类结合肽库，MHC I类稳定和T细胞功能调节的肽加载络合物的贡献。

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。