Role of the BLTR1 receptor in lymphocyte trafficking

描述（由申请人提供）：通过拟议的指导临床科学家发展奖，申请人将建立在她之前研究抗原特异性人CD 8+细胞的经验基础上，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·卢斯特博士将指导首席研究员的科学发展。 Luster博士是趋化因子生物学领域公认的领导者。他是流变学，过敏和免疫学的负责人，并培养了许多博士后研究员。Luster博士的实验室将提供一个丰富的知识环境，以促进候选人的科学发展，实现她独立调查的目标。拟议的研究将为申请人提供利用体内分子遗传学方法研究T淋巴细胞运输基本问题的机会。白细胞的募集和激活对于协调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靶点。 白三烯B4（LTB 4）是一种主要由骨髓细胞合成的有效脂质化学引诱剂。申办方将小鼠BLTR 1鉴定为LTB 4的高亲和力受体，并生成了BLTR 1基因靶向缺失的小鼠品系。 虽然BLTR 1已被描述为介导LTB 4功能的骨髓细胞上的重要功能性受体，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，申请人已经证明BLTR 1在效应CD 4+和CD 8 + T细胞中的体外T细胞活化时被诱导。来自人类受试者和动物模型的其他初步数据表明，表达BLTR 1的T淋巴细胞可能被募集到炎症部位。申请人将研究新的假设，即BLTR 1和LTB 4对于效应T细胞运输到炎症部位是重要的，因此用于将获得性免疫应答与先天免疫细胞如嗜中性粒细胞和巨噬细胞的激活联系起来。申请人特别提出：（1）确定BLTR 1在体内抗原产生的CD 4+和CD 8+运输中的作用;（2）确定BLTR 1在Th 1和Th 2细胞运输中的作用;（3）确定BLTR 1在单核细胞增生李斯特菌感染的鼠模型中效应CD 8+细胞运输中的作用;（4）确定BLTR 1表达是否定义了人效应T细胞的独特群体。

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.