Chemokine receptors and the interferon gamma pathway in Th1 cell trafficking

Th1 细胞运输中的趋化因子受体和干扰素 γ 通路

• 批准号: 7254193
• 负责人: ZAMANEH MIKHAK
• 金额: $ 13.01万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254193
• 关键词: Adoptive Transfer; Affect; Anatomic Sites; Antibodies; Antigens; Autoimmune Process; Bone Marrow; Bone Marrow Transplantation; CCR1 gene; CCR5 gene; CXCL10 gene; CXCL9 gene; CXCR3 gene; CXCR6 gene; Cells; Cellular Immunology; Data; Disease; Flow Cytometry; Goals; Hematopoietic; Homing; Immunohistochemistry; In Vitro; Infection; Inflammation; Inflammatory; Injury; Interferon Type II; Interferons; Laboratories; Lead; Learning; Ligand Binding; Ligands; Lung; Lymphocyte; Mediating; Mentored Clinical Scientist Development Award (K08); Mentorship; Molecular and Cellular Biology; Mus; Ovalbumin; Pathway interactions; Play; Polymerase Chain Reaction; Prevention; Range; Research; Research Personnel; Research Training; Role; STAT1 gene; STAT6 gene; Signal Transduction; Site; Source; Staining method; Stains; Stream; T-Lymphocyte; Techniques; Th1 Cells; Th2 Cells; Time; Tissues; Wild Type Mouse; career; chemokine; chemokine receptor; experience; in vivo; insight; interferon gamma receptor; interferon gamma receptors; receptor; receptor expression; reconstitution; research study; trafficking; transcription factor

DESCRIPTION (provided by applicant): Homing of Th1 cells to sites of Th1 inflammation relies on the interaction of chemokine receptors on Th1 cells with the chemokines secreted at Th1 inflammatory sites. We present preliminary data that STAT1 is the master regulator of Th1 cell trafficking as STAT1-deficiency, but not T-bet deficiency, dramatically impairs the recruitment of adoptively transferred wild-type antigen-specific Th1 cells to inflammatory sites. STAT1 controls Th1 cell trafficking by regulating tissue expression of a subset of chemokines. Finally, antigen-specific Th1 cells that traffic to inflammatory sites preferentially express a select group of chemokine receptors. It is not clear, at this point, which one of these chemokine receptors are critical for trafficking of antigen-specific Th1 cells or what aspect of Th1 inflammation drives the expression of these chemokine receptors on Th1 cells. We hypothesize that a distinct subset of chemokine receptors expressed on antigen-specific Th1 cells is critical for effective trafficking of antigen-specific Th1 cells and that the interferon gamma pathway plays a regulatory role in the expression of these chemokine receptors. We propose to: 1) Determine the cellular source of STAT1, and relevant chemokines, that is critical for recruitment of antigen-specific Th1 cells, using immunohistochemistry staining and bone marrow transplantation experiments. 2) Determine the subset of chemokine receptors that is critical for effective trafficking of antigen-specific Th1 cells in vivo, using adoptive transfer of wild type and chemokine receptor deficient antigen-specific Th1 cells. 3) Determine whether interferon gamma, and/or the transcription factors down stream of interferon gamma signaling, regulate the expression of chemokine receptors on antigen-specific Th1 cells, using in vitro generated antigen-specific Th1 cells deficient in the interferon gamma receptor, STAT1 or T-bet, and quantitative PCR and flow cytometry. With this Mentored Clinical Scientist Development Award, I will build upon my previous training and research experiences, learn a variety of laboratory techniques in immunology, cell and molecular biology and study mechanisms that control Th1 cell trafficking. I will benefit from the mentorship of Dr. Andrew D. Luster, an expert in fileds of chemokines and effector T cell trafficking. My ultimate goal is to focus my research career as an independent investigator on mechanisms of T cell recruitment. As effector T cells orchestrate a wide range of disorders, a better understanding of the pathways that lead to T cell trafficking has far reaching potential benefits for the treatment and prevention of infectious, autoimmune and atopic diseases.

描述(由申请人提供)：Th1细胞归巢到Th1炎症部位依赖于Th1细胞上的趋化因子受体与Th1炎症部位分泌的趋化因子的相互作用。我们提供的初步数据表明，STAT1是Th1细胞运输的主要调节者，因为STAT1缺乏，而不是T-bet缺乏，显著损害过继转移的野生型抗原特异性Th1细胞向炎症部位的募集。STAT1通过调节一组趋化因子的组织表达来控制Th1细胞的运输。最后，运输到炎症部位的抗原特异性Th1细胞优先表达一组选定的趋化因子受体。目前尚不清楚这些趋化因子受体中的哪一个对抗原特异性Th1细胞的运输至关重要，也不清楚Th1炎症的哪个方面驱动了Th1细胞上这些趋化因子受体的表达。我们假设，抗原特异性Th1细胞上表达的一组不同的趋化因子受体对抗原特异性Th1细胞的有效运输至关重要，干扰素伽马途径在这些趋化因子受体的表达中起着调节作用。我们建议：1)通过免疫组织化学染色和骨髓移植实验，确定STAT1的细胞来源和相关的趋化因子，这对抗原特异性Th1细胞的募集至关重要。2)通过过继转移野生型和趋化因子受体缺陷的抗原特异性Th1细胞，确定在体内有效转运抗原特异性Th1细胞所需的趋化因子受体亚群。3)使用体外产生的缺乏干扰素γ受体的抗原特异性Th1细胞，STAT1或T-bet，以及定量聚合酶链式反应和流式细胞术，确定干扰素γ和/或干扰素γ信号下游的转录因子是否调节抗原特异性Th1细胞上趋化因子受体的表达。有了这个有指导的临床科学家发展奖，我将在我以前的培训和研究经验的基础上，学习免疫学、细胞和分子生物学的各种实验室技术，并研究控制Th1细胞运输的机制。我将受益于安德鲁·D·卢斯特博士的指导，他是趋化因子和效应器T细胞贩运领域的专家。我的最终目标是将我作为一名独立研究员的研究生涯集中在T细胞招募的机制上。由于效应性T细胞可以协调多种疾病，因此更好地了解导致T细胞转运的途径对于治疗和预防传染病、自身免疫性疾病和特应性疾病具有深远的潜在益处。