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: 7436247
• 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/7436247
• 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）：Th 1细胞归巢至Th 1炎症部位依赖于Th 1细胞上的趋化因子受体与Th 1炎症部位分泌的趋化因子的相互作用。我们目前的初步数据表明，STAT 1是主要的调节因子的Th 1细胞贩运的STAT 1缺陷，但不是T-bet缺陷，大大削弱了募集过继转移的野生型抗原特异性Th 1细胞的炎症部位。STAT 1通过调节趋化因子亚群的组织表达来控制Th 1细胞的运输。最后，抗原特异性Th 1细胞，交通炎症部位优先表达一组选择的趋化因子受体。目前尚不清楚这些趋化因子受体中的哪一种对于抗原特异性Th 1细胞的运输至关重要，或者Th 1炎症的哪一方面驱动Th 1细胞上这些趋化因子受体的表达。我们假设，抗原特异性Th 1细胞上表达的趋化因子受体的一个独特的子集是抗原特异性Th 1细胞的有效运输的关键，干扰素γ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）使用免疫组织化学染色和骨髓移植实验，确定STAT 1和相关趋化因子的细胞来源，其对于抗原特异性Th 1细胞的募集至关重要。2)使用野生型和趋化因子受体缺陷型抗原特异性Th 1细胞的过继转移，确定对抗原特异性Th 1细胞在体内有效运输至关重要的趋化因子受体亚群。3)确定干扰素γ和/或干扰素γ信号传导下游的转录因子是否调节抗原特异性Th 1细胞上趋化因子受体的表达，使用体外产生的干扰素γ受体、STAT 1或T-bet缺陷的抗原特异性Th 1细胞，以及定量PCR和流式细胞术。有了这个指导临床科学家发展奖，我将建立在我以前的培训和研究经验，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Th 1细胞贩运的机制。我将受益于安德鲁博士的指导。Luster是趋化因子和效应T细胞运输领域的专家。我的最终目标是把我的研究生涯作为一个独立的研究者T细胞募集的机制。由于效应T细胞协调广泛的疾病，更好地理解导致T细胞运输的途径对于治疗和预防感染性、自身免疫性和特应性疾病具有深远的潜在益处。