Role of a4b7 integrin/MAdCAM-1 interaction in hematopoietic stem cell trafficking

a4b7 整合素/MAdCAM-1 相互作用在造血干细胞运输中的作用

• 批准号: 8763878
• 负责人: JODI LEHIWA KAZUYO MURAKAMI
• 金额: $ 2.71万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8763878
• 关键词: Binding; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Cell Adhesion Molecules; Cells; Clinical; Clinical Protocols; Coupled; Data; Endothelial Cells; Engraftment; Genes; Goals; Health; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Homing; In Vitro; Integrins; Knowledge; Leukocytes; Ligands; Link; Mediating; Molecular; Mus; Myelosuppression; Patients; Pattern; Population; Process; Research; Role; Spleen; Testing; Tissues; Transplantation; Vascular Endothelium; Work; base; bone; cytokine; differential expression; hematopoietic tissue; improved; in vivo; innovation; migration; mucosal addressin cell adhesion molecule-1; mutant; novel strategies; novel therapeutics; prevent; reconstitution; stem cell biology; success; trafficking

DESCRIPTION (provided by applicant): After hematopoietic stem cell (HSC) transplantation, the first step necessary to attain successful engraftment and repopulation of all hematopoietic lineages is the migration and homing of donor HSCs to the bone marrow (BM) of the myelosuppressed recipient. HSC homing proceeds through a multistep process involving direct interactions between circulating cells and endothelial cells that are mediated by cell adhesion molecules. Although a few adhesion molecules have been linked to various steps of the HSC homing process, the mechanisms underlying the differential expression of adhesion molecules and how this influences HSC trafficking and subsequent engraftment remain poorly understood. We have recently identified a small subpopulation of HSCs in the BM that express ß7 integrin at steady state. From our preliminary studies, we found that these ß7+ HSCs are capable of multilineage, long-term reconstitution of irradiated hosts and increased engraftment potential when in direct competition with ß7-HSCs. We discovered that blockade of the α4ß7 integrin ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), in lethally irradiated recipients prevented engraftment of long-term reconstituting HSCs after transplantation. Therefore, we hypothesize that the α4ß7 integrin/MAdCAM-1 interaction is essential for the homing process of donor HSCs to the BM of myelosuppressed recipients. To test this hypothesis, we propose to: 1) determine the expression of MAdCAM- 1 and ß7 integrin within the BM and spleen microenvironments following myelosuppression; 2) define the function of ß7 integrin and MAdCAM-1 in the trafficking of HSCs in vivo. The long-term goals of this project are to define the molecular interactions that regulate the homing of HSCs and elucidate how these molecules influence HSC trafficking and subsequent engraftment.

描述（由申请人提供）：造血干细胞（HSC）移植后，实现所有造血谱系成功植入和再增殖所需的第一步是供体HSC迁移和归巢至骨髓抑制受体的骨髓（BM）。HSC归巢是一个多步骤的过程，涉及循环细胞和内皮细胞之间由细胞粘附分子介导的直接相互作用。虽然一些粘附分子已被链接到HSC归巢过程的各个步骤，粘附分子的差异表达的机制，以及如何影响HSC的运输和随后的植入仍然知之甚少。我们最近在BM中鉴定了一小部分HSC亚群，其在稳定状态下表达β 7整联蛋白。从我们的初步研究中，我们发现这些β 7 + HSC在与β 7-HSC直接竞争时能够多谱系、长期重建受照射的宿主并增加植入潜力。我们发现，在接受致死剂量照射的受者中，阻断α 4 β 7整联蛋白配体、粘膜地址素细胞粘附分子1（MAdCAM-1）可阻止移植后长期重建的HSC的植入。因此，我们假设α 4 β 7整联蛋白/MAdCAM-1相互作用对于供体HSC向骨髓抑制受体BM的归巢过程是必需的。为了验证这一假设，我们建议：1）确定骨髓抑制后BM和脾微环境中MAdCAM- 1和β 7整联蛋白的表达; 2）确定β 7整联蛋白和MAdCAM-1在体内HSC运输中的功能。该项目的长期目标是确定调节HSC归巢的分子相互作用，并阐明这些分子如何影响HSC的运输和随后的植入。