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: 7627204
• 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/7627204
• 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; Prevention; 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细胞归巢至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因子，因为 STAT1 缺陷而非 T-bet 缺陷会显着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 通过调节趋化因子子集的组织表达来控制 Th1 细胞运输。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于抗原特异性 Th1 细胞的运输至关重要，或者 Th1 炎症的哪个方面驱动这些趋化因子受体在 Th1 细胞上的表达。我们假设抗原特异性 Th1 细胞上表达的趋化因子受体的独特子集对于抗原特异性 Th1 细胞的有效运输至关重要，并且干扰素 γ 途径在这些趋化因子受体的表达中发挥调节作用。我们建议：1) 使用免疫组织化学染色和骨髓移植实验确定 STAT1 和相关趋化因子的细胞来源，这对于招募抗原特异性 Th1 细胞至关重要。 2) 使用野生型和趋化因子受体缺陷型抗原特异性 Th1 细胞的过继转移，确定对抗原特异性 Th1 细胞在体内有效运输至关重要的趋化因子受体子集。 3) 使用体外生成的缺乏干扰素γ受体、STAT1或T-bet的抗原特异性Th1细胞，以及定量PCR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。凭借这一指导性临床科学家发展奖，我将在之前的培训和研究经验的基础上，学习免疫学、细胞和分子生物学方面的各种实验室技术，并研究控制 Th1 细胞运输的机制。我将受益于趋化因子和效应 T 细胞贩运领域专家 Andrew D. Luster 博士的指导。我的最终目标是作为一名独立研究者，将我的研究生涯集中在 T 细胞招募机制上。由于效应 T 细胞协调多种疾病，更好地了解导致 T 细胞运输的途径对于治疗和预防传染性、自身免疫性和特应性疾病具有深远的潜在益处。