Role of Chat-H in chemokine-induced T lymphocyte migration and trafficking

Chat-H 在趋化因子诱导的 T 淋巴细胞迁移和运输中的作用

基本信息

批准号：
8076331
负责人：
KONSTANTINA ALEXANDROPOULOS
金额：
$ 40.74万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8076331
关键词：
Ablation Adaptor Signaling Protein Address Adhesions Affect Affinity Allergic Disease Bacterial Infections Biochemical Cell Adhesion Cell Lineage Cell physiology Cell-Cell Adhesion Cells Chemotaxis Chronic Complex Defect Development Disease Doctor of Philosophy Down-Regulation Exhibits Future Genetic Guanosine Triphosphate Phosphohydrolases Homing Immigration Immune response In Vitro Inflammation Integrin Inhibition Integrin-mediated Cell Adhesion Pathway Integrins Interleukin-2 Knockout Mice Lead Leukocyte Adhesion Deficiency Leukocytes Lymph Lymphocyte Lymphoid Mature T-Lymphocyte Mediating Molecular Morphology Mus Organ Patients Peripheral Physiological Plague Play Process Production Proteins RNA Interference Receptor Signaling Recurrence Research Personnel Role Secondary to Signal Pathway Signal Transduction Signaling Protein Subfamily lentivirinae T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Thymocyte Development Thymocyte Selection Time Tissues cell mediated immune response cell motility chemokine chemokine receptor human disease in vivo insight migration novel programs receptor-mediated signaling research study response therapeutic target thymocyte trafficking

项目摘要

DESCRIPTION (provided by applicant): In this application we propose to examine the role of the novel protein Chat-H in signaling pathways that regulate T lymphocyte migration. In preliminary studies, we used lentivirus-mediated RNA interference (RNAi) to silence expression of Chat-H in mouse primary T cells and study the effect of Chat-H deletion on T cell function. We found that whereas Chat-H downregulation had no effect on T cell receptor (TCR)-mediated signaling, in vitro and in vivo chemokine-induced migration of Chat-H deficient T cells was dramatically impaired. Defects in migration and adhesion correlated with impaired activation of the Rap-1 GTPase, which is a key regulator of integrin-mediated cellular adhesion and migration. Chat-H constitutively associated with the signaling protein CasL and formation of this complex was necessary for migration. These observations suggest that Chat-H is an important regulator of chemokine receptor signaling and T lymphocyte migration and it that it acts together with CasL to regulate these processes. To study the in vivo requirement for Chat-H we recently generated Chat-H knockout mice and consistent with previous results, preliminary studies show that T cells from these mice exhibit impaired in vitro migration. In the experiments described here, we propose to examine the mechanisms through which Chat-H regulates chemokine-induced T lymphocyte migration and the effect of Chat-H deficiency in this process. We will test the following hypothesis: Chat-H regulates chemokine-induced T lymphocyte migration by activating Rap1 and Rap1-mediated integrin activation, cell adhesion and migration. Deficiency in Chat-H expression results in defective integrin-mediated adhesion and as a result impaired homeostatic homing of T cells to secondary lymphoid organs, and compromised T-cell-mediated immune responses. To test this hypothesis we will use first use T cells in which Chat-H has been dowregulated by RNAi to define the biochemical mechanisms of how Chat-H regulates Rap1 activation and integrin-mediated adhesion. To study the in vivo requirement for Chat-H we will use Chat-H knockout mice to determine whether Chat-H deficiency affects in vivo migration and homeostatic trafficking of mature T cells to peripheral lymphoid organs, and T-cell-mediated immune responses. We anticipate that these experiments will lead to novel insight into the mechanisms that regulate lymphocyte chemotaxis and reveal important roles for both Chat-H and CasL in this process downstream of chemokine receptors. Through these studies we also aim towards gaining insight into the role of Chat-H in chronic inflammation and conditions associated with leukocyte adhesion deficiencies and identify therapeutic targets for treating human diseases.

描述（由申请人提供）：在本申请中，我们建议检查新型蛋白质 Chat-H 在调节 T 淋巴细胞迁移的信号通路中的作用。在初步研究中，我们使用慢病毒介导的RNA干扰（RNAi）来沉默小鼠原代T细胞中Chat-H的表达，并研究Chat-H缺失对T细胞功能的影响。我们发现，尽管 Chat-H 下调对 T 细胞受体 (TCR) 介导的信号传导没有影响，但体外和体内趋化因子诱导的 Chat-H 缺陷 T 细胞的迁移却受到显着损害。迁移和粘附缺陷与 Rap-1 GTPase 激活受损相关，Rap-1 GTPase 是整合素介导的细胞粘附和迁移的关键调节因子。 Chat-H 与信号蛋白 CasL 组成型相关，并且该复合物的形成对于迁移是必需的。这些观察结果表明，Chat-H 是趋化因子受体信号传导和 T 淋巴细胞迁移的重要调节因子，并且它与 CasL 一起调节这些过程。为了研究 Chat-H 的体内需求，我们最近生成了 Chat-H 敲除小鼠，与之前的结果一致，初步研究表明这些小鼠的 T 细胞表现出体外迁移受损。在此描述的实验中，我们建议检查 Chat-H 调节趋化因子诱导的 T 淋巴细胞迁移的机制以及 Chat-H 缺陷在此过程中的影响。我们将检验以下假设：Chat-H 通过激活 Rap1 和 Rap1 介导的整合素激活、细胞粘附和迁移来调节趋化因子诱导的 T 淋巴细胞迁移。 Chat-H 表达缺陷会导致整合素介导的粘附缺陷，从而损害 T 细胞向次级淋巴器官的稳态归巢，并损害 T 细胞介导的免疫反应。为了检验这一假设，我们将首先使用 Chat-H 已被 RNAi 下调的 T 细胞来定义 Chat-H 如何调节 Rap1 激活和整合素介导的粘附的生化机制。为了研究 Chat-H 的体内需求，我们将使用 Chat-H 敲除小鼠来确定 Chat-H 缺陷是否影响成熟 T 细胞向外周淋巴器官的体内迁移和稳态运输，以及 T 细胞介导的免疫反应。我们预计这些实验将对调节淋巴细胞趋化性的机制产生新的见解，并揭示 Chat-H 和 CasL 在趋化因子受体下游这一过程中的重要作用。通过这些研究，我们还旨在深入了解 Chat-H 在慢性炎症和白细胞粘附缺陷相关病症中的作用，并确定治疗人类疾病的治疗靶点。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1.

DOI：
10.1161/atvbaha.116.308014
发表时间：
2016-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Herbin O;Regelmann AG;Ramkhelawon B;Weinstein EG;Moore KJ;Alexandropoulos K
通讯作者：
Alexandropoulos K

Impaired central tolerance induces changes in the gut microbiota that exacerbate autoimmune hepatitis.

DOI：
10.1016/j.jaut.2022.102808
发表时间：
2022-04
期刊：
Journal of autoimmunity
影响因子：
12.8
作者：
Centa M;Weinstein EG;Clemente JC;Faith JJ;Fiel MI;Lyallpuri R;Herbin O;Alexandropoulos K
通讯作者：
Alexandropoulos K

Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model.