Role of the BLTR1 receptor in lymphocyte trafficking

BLTR1 受体在淋巴细胞运输中的作用

• 批准号: 6804723
• 负责人: SABINA A ISLAM
• 金额: $ 11.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804723
• 关键词: Listeria infections; T lymphocyte; cell migration; cell surface receptors; human tissue; laboratory mouse; leukocyte activation /transformation; leukotrienes; receptor expression; Listeria infections; T lymphocyte; cell migration; cell surface receptors; human tissue; laboratory mouse; leukocyte activation /transformation; leukotrienes; receptor expression

DESCRIPTION (provided by applicant): With the proposed Mentored Clinical Scientist Development Award, the applicant will build upon her prior experiences studying antigen-specific human CD8+ cells to expand her scientific skills in immunology, cell biology and molecular biology. Dr. Andrew Luster will mentor the principal investigator's scientific development. Dr. Luster is a recognized leader in the field of chemokine biology. He is the Chief of Rheumatology, Allergy and Immunology and has trained numerous postdoctoral fellows. The laboratory of Dr. Luster will provide a rich intellectual environment to foster the candidate's scientific development toward her goal of independent investigation. The proposed study will provide the applicant with an opportunity to utilize in vivo molecular genetic approaches to study basic questions in T lymphocyte trafficking. Leukocyte recruitment and activation are critical for orchestrating host inflammatory responses, and mediators regulating these responses are attractive targets for therapeutic intervention. Leukotriene B4 (LTB4) is a potent lipid chemo-attractant synthesized primarily by myeloid cells. The sponsor identified murine BLTR1 as the high affinity receptor for LTB4 and generated a mouse strain with a targeted deletion of the BLTR1 gene. While BLTR1 has been described as an important functional receptor on myeloid cells that mediates LTB4 function, its expression and function on T cells has not been previously characterized. In preliminary experiments the applicant has demonstrated that BLTR1 is induced upon in vitro T cell activation in effector CD4+ and CD8+ T cells. Additional preliminary data from human subjects and animal models suggests that BLTR1 expressing T lymphocytes may be recruited to sites of inflammation. The applicant will investigate the novel hypothesis that BLTR1 and LTB4 are important for effector T cell trafficking to inflammatory sites, thus serving to link the acquired immune response to the activation of innate immune cells such as neutrophils and macrophages. The applicant specifically proposes to: (1) determine the role of BLTR1 in antigen generated CD4+ and CD8+ trafficking in vivo; (2) determine the role of BLTR1 in Th1 and Th2 cell trafficking; (3) determine the role of BLTR1 in effector CD8+ cell trafficking in a murine model of Listeria monocytogenes infection; (4) determine if BLTR1 expression defines a unique population of human effector T cells.

描述（由申请人提供）：在拟议的指导临床科学家发展奖中，申请人将基于她先前研究抗原特异性人CD8+细胞的经验，以扩大她在免疫学，细胞生物学和分子生物学方面的科学技能。安德鲁·劳斯特（Andrew Luster）博士将指导主要研究者的科学发展。 Luster博士是趋化因子生物学领域的公认领导者。他是风湿病，过敏和免疫学的负责人，并培训了许多博士后研究员。 Luster博士的实验室将提供丰富的知识环境，以促进候选人的科学发展，以实现独立调查的目标。拟议的研究将为申请人提供利用体内分子遗传学方法来研究T淋巴细胞运输中的基本问题的机会。白细胞募集和激活对于策划宿主炎症反应至关重要，调节这些反应的介质是治疗干预的有吸引力的目标。 白三烯B4（LTB4）是一种主要由髓样细胞合成的有效脂质化学吸收剂。赞助商将鼠BLTR1鉴定为LTB4的高亲和力受体，并产生具有BLTR1基因的靶向缺失的小鼠菌株。 尽管BLTR1被描述为介导LTB4功能的髓样细胞上的重要功能受体，但其在T细胞上的表达和功能先前尚未被表征。在初步实验中，申请人表明，在效应子CD4+和CD8+ T细胞中的体外T细胞激活后诱导BLTR1。来自人类受试者和动物模型的其他初步数据表明，表达T淋巴细胞的BLTR1可能会被募集到炎症部位。申请人将研究新的假设，即BLTR1和LTB4对于效应T细胞运输至炎症部位很重要，从而将获得的免疫反应与先天免疫细胞（如中性粒细胞和巨噬细胞）的激活联系起来。申请人专门提出：（1）确定BLTR1在体内产生的CD4+和CD8+运输中的作用； （2）确定BLTR1在Th1和Th2细胞运输中的作用； （3）确定BLTR1在效应子CD8+细胞运输中的作用在单核细胞增生李斯特氏菌感染的鼠模型中； （4）确定BLTR1表达是否定义了人类效应T细胞的独特群体。