Cell Signaling of Host Defense

由Michael B. Fessler博士领导的国立环境健康科学研究所校内研究部呼吸生物学实验室宿主防御小组，自成立以来已进入NIEHS的第二年。我们已经将我们的工作人员增加到4名活跃的实验室成员，并预计在未来2个月内再增加2名博士后加入我们的团队。此外，我们已经提交了一个竞争性的内部董事挑战项目，如果获奖，将为我们的团队提供资源，以聘请2名额外的研究员，并将我们的巨噬细胞先天免疫研究扩展到动脉粥样硬化应用。取得的成就包括：《免疫学杂志》上一篇正在修订的原稿，该原稿定义了核受体肝X受体在肺先天免疫调节中的新作用，一篇关于类似材料的会议摘要即将在《美国胸科学会会刊》上发表，两篇中间作者合作发表的论文（J Immunol, J All clinimmunol），以及一篇邀请同行评议的关于肝脏X受体的文章，目前信号转导治疗正在审查中。他的其他成就还包括获得2008年FARE抽象奖给苏拉杰·Dhungana研究员，并通过竞争成功地向美国国立卫生研究院罕见疾病办公室申请资助，以支持由PI主持的基于niehs的脂质筏生物学研讨会，该研讨会还将与他主持的在筏生物学领域世界知名的杰出讲师Kai Simons相一致。去年，PI分别在国际、国家和区域会议上发表了三次讲话。此外，在实验室的5个活跃研究项目中收集了大量数据：1)载脂蛋白a - i作为先天免疫的新刺激的表征；2)载脂蛋白a - i和E在小鼠吸入LPS模型中作为肺部先天免疫的新型内源性调节因子的特性；3)蛋白质组学发现巨噬细胞脂筏响应LPS的新信号蛋白（后一项工作导致了几个靶点，目前正在进行功能验证，以确定它们在巨噬细胞中使用RNAi介导LPS信号级联中的作用）；4)确定高胆固醇饮食对吸入LPS小鼠肺先天免疫的调节作用。此外，已经获得了几种缺乏选定的胆固醇运输调节因子的小鼠品系，或者重新衍生和繁殖，或者目前正在进行重新衍生，目的是将它们用作工具，以阐明这些调节靶点在体内肺先天免疫中的作用。最后，我们相信我们已经确定了一种新型的病毒来源的TLR4激动剂，我们计划在雇用博士后研究员之前进一步表征和验证。目前正在编写2份新的原稿。

The Host Defense Group of the Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, headed by Michael B. Fessler, MD now enters its second year at the NIEHS since inception. We have increased our staffing to 4 active laboratory members, and expect another 2 postdocs to join the group within the next 2 months. Moreover, we have submitted a project on a competitive intramural Direcors Challenge Program that, if awarded, will provide our Group with resources to hire 2 additional fellows and to extend our macrophage innate immunity work into atherosclerosis applications. Accomplishments include an original manuscript currently under revision for Journal of Immunology that defines novel roles for the nuclear receptor Liver X Receptor in modulation of pulmonary innate immunity, a meeting abstract on similar material in press to be published in the Proceedings of the American Thoracic Society, 2 middle-author collaborative publications (J Immunol, J All Clin Immunol), and an invited peer-reviewed review article on Liver X Receptor under review for Current Signal Transduction Therapy. Additional accomplishments include a 2008 FARE abstract award for Research Fellow Suraj Dhungana, and a successful competitive application to the NIH Office of Rare Diseases to secure supportive funding for an NIEHS-based symposium on lipid raft biology to be chaired by the PI, that will also correspond with his hosting of a Distinguished Lectureship speaker world-renowned in field of raft biology, Kai Simons. Three talks were delivered by the PI at international, national, and regional meetings, respectively, during the last year. In addition, substantial data has been collected on 5 active research projects in the laboratory: 1) characterization of apoplipoprotein A-I as a novel stimulus of innate immunity; 2) characterization of apolipoproteins A-I and E as novel endogenous regulators of pulmonary innate immunity in a murine model of inhaled LPS; 3) proteomic discovery of novel signaling proteins recruited to macrophage lipid rafts in response to LPS (this latter work has led to several targets which are currently undergoing functional validation for a role in the LPS signaling cascade with the use of RNAi in macrophages); and 4) identification of a modulatory role of high-cholesterol diet upon pulmonary innate immunity in a murine model of inhaled LPS. In addition, several mouse strains deficient in selected regulators of cholesterol trafficking have been procured and either rederived and bred, or are currently undergoing rederivation with an eye towards using them as tools to clarify a role for these regulatory targets in pulmonary innate immunity in vivo. Finally, we believe we have identified a novel TLR4 agonist of viral origin that we plan to characterize and validate further pending the hire of a postdoctoral fellow. Presently, 2 new original manuscripts are under preparation.