Role of the BLTR1 receptor in lymphocyte trafficking

申请者描述(由申请者提供)：通过建议的临床科学家指导发展奖，申请者将以她以前研究抗原特异性人类CD8细胞的经验为基础，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·卢斯特博士将指导首席研究员的科学发展。勒斯特博士是趋化因子生物学领域公认的领导者。他是风湿病、过敏和免疫学主任，培养了许多博士后研究员。卢斯特博士的实验室将提供丰富的智力环境，促进候选人朝着独立研究目标的科学发展。这项拟议的研究将为申请者提供一个利用体内分子遗传学方法来研究T淋巴细胞贩运的基本问题的机会。白细胞募集和激活是协调宿主炎症反应的关键，调节这些反应的介质是治疗干预的有吸引力的靶点。白三烯B4(LTB4)是一种主要由髓系细胞合成的强脂类化学诱导剂。赞助商确定小鼠BLTR1是LTB4的高亲和力受体，并产生了一种靶向缺失BLTR1基因的小鼠品系。虽然BLTR1已被描述为介导LTB4功能的髓系细胞上的重要功能受体，但其在T细胞上的表达和功能尚未被研究过。在初步实验中，申请人已经证明了BLTR1是在体外T细胞激活效应的CD4和CD8T细胞上被诱导的。来自人类受试者和动物模型的其他初步数据表明，表达BLTR1的T淋巴细胞可能被招募到炎症部位。申请人将研究新的假设，即BLTR1和LTB4对于效应T细胞向炎症部位的运输非常重要，从而将获得性免疫反应与中性粒细胞和巨噬细胞等先天免疫细胞的激活联系起来。申请人特别建议：(1)确定BLTR1在体内抗原产生的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)在单核细胞增多性李斯特菌感染的小鼠模型中确定BLTR1在效应CD8细胞运输中的作用；(4)确定BLTR1的表达是否定义了独特的人类效应T细胞群。

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.