Structure Function Analysis of T Cell E-Selectin Ligands

T细胞E-选择素配体的结构功能分析

• 批准号: 6671720
• 负责人: ROBERT C FUHLBRIGGE
• 金额: $ 11.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6671720
• 关键词: CD43 molecule; SDS polyacrylamide gel electrophoresis; T lymphocyte; binding sites; cell adhesion; cellular immunity; clinical research; glycoproteins; human tissue; inflammation; leukocytes; ligands; mass spectrometry; protein structure function; proteolysis; selectins; skin; western blottings

DESCRIPTION (provided by applicant): Recruitment of leukocytes from blood into cutaneous inflammatory sites occurs via a stepwise cascade of adhesion events. T cell trafficking to sites of cutaneous inflammation has been closely associated with expression of the cutaneous lymphocyte antigen (CLA), a carbohydrate epitope that serves as an E-selectin ligand on T cells and mediates the first, crucial steps in T cell recruitment. CLA has been shown previously to be differentially expressed on a leukocyte sialomucin called P-selectin glycoprotein ligand-1 (PSGL-1). We have recently discovered that CD43, a sialomucin similar in structure to PSGL-1, and an unidentified 100kD sialoglycoprotein (gpl00) can also serve as E-selectin ligands on CLA+ T cells. These previously unknown T cell selectin ligands were identified using two novel assay methods we have developed. There is, at present, no published data regarding the structure or regulation of E-selectin ligand determinants on CD43 or a 100 kD glycoprotein on T cells. These previously unknown ligands may play important, currently undefined roles in immune surveillance and the recruitment of leukocytes to inflammatory loci. In this application, we outline experiments that will characterize the individual E-selectin ligands expressed on T cells. The identification of common motifs among these ligands could lead directly to the design and development of common inhibitors of E-selectin mediated adhesion that may be of significant value in inflammatory disorders such as chronic autoimmune disease, graft-versus-host disease and transplantation rejection.

描述（由申请人提供）：白细胞从血液中募集到皮肤炎症部位是通过粘附事件的逐步级联发生的。T细胞运输到皮肤炎症部位与皮肤淋巴细胞抗原（CLA）的表达密切相关，CLA是一种碳水化合物表位，作为T细胞上的e -选择素配体，介导T细胞募集的第一步，也是关键步骤。CLA先前已被证明在称为p -选择素糖蛋白配体-1 （PSGL-1）的白细胞唾液蛋白上有差异表达。我们最近发现，与PSGL-1结构相似的唾液蛋白CD43和一种未识别的100kD唾液糖蛋白（gpl00）也可以作为CLA+ T细胞上的e -选择素配体。这些以前未知的T细胞选择素配体是用我们开发的两种新的测定方法鉴定的。目前，还没有关于T细胞上CD43或100kd糖蛋白上e -选择素配体决定因子的结构或调控的公开数据。这些以前未知的配体可能在免疫监视和白细胞募集到炎症位点中发挥重要作用，目前尚未明确。在这个应用中，我们概述了将表征在T细胞上表达的单个e -选择素配体的实验。识别这些配体之间的共同基序可以直接导致设计和开发e -选择素介导的常见粘附抑制剂，这可能在炎症性疾病，如慢性自身免疫性疾病、移植物抗宿主病和移植排斥反应中具有重要价值。