Surfactant Protein D in Pulmonary and Systemic Host Defense

描述（由申请人提供）： 表面活性剂蛋白D（SP-D）是胶原凝集素蛋白家族的成员。在肺中，SP-D结合细菌、病毒和真菌病原体，并促进这些微生物的清除。SP-D还结合炎性分子，如脂多糖，并限制这些分子诱导的炎性损伤。由于其在肺免疫系统中的作用，SP-D正在被开发为一种治疗剂，旨在限制肺部微生物的生长和由此产生的炎症损伤。SP-D也在许多非肺部位产生;然而，肺外SP-D的来源和功能尚不清楚。我们的初步研究结果表明，SP-D也参与了系统的主机防御。因此，本申请试图检验SP-D在清除全身性病原体中起作用并调节全身性宿主防御的一般假设。为了验证这一假设，我们将确定静脉注射SP-D是否能改善暴露于脂多糖或活细菌挑战的小鼠的炎症、组织损伤和存活率。我们将确定系统性SP-D的产生和清除位点以及控制系统性SP-D产生的转录机制。我们将确定调节系统性宿主防御细胞所需的SP-D的结构特征。这些研究将促进我们对SP-D在系统性宿主防御中的作用的理解。此外，这些研究将为未来的转化研究奠定基础，以测试SP-D治疗全身感染和脓毒性休克。该基金的主要研究者已完成博士学位。在生物化学，临床奖学金，在泌尿科，目前是助理教授在新生儿科，围产期和肺生物学。在整个培训过程中，他一再表现出对科学研究事业的承诺。本补助金中概述的实验和培训将显著拓宽主要研究者的技能和知识，并促进他发展成为独立的临床科学家。

DESCRIPTION (provided by applicant): Surfactant protein D (SP-D) is a member of the collectin family of proteins. In the lung, SP-D binds bacterial, viral, and fungal pathogens and facilitates the clearance of these organisms. SP-D also binds inflammatory molecules, such as lipopolysaccharide, and limits the inflammatory damage that these molecules induce. As a consequence of its role in the lung immune system, SP-D is being developed as a therapeutic agent designed to limit the growth of microorganisms in the lung and the resulting inflammatory damage. SP-D is also produced in many non-pulmonary locations; however, the source and functions of extrapulmonary SP-D are unknown. Our preliminary results suggest that SP-D is also involved in systemic host defense. Therefore, this application seeks to test the general hypothesis that SP-D plays a role in the clearance of systemic pathogens and regulates systemic host defense. To test this hypothesis we will determine if intravenously injected SP-D improves inflammation, tissue damage and survival in mice exposed to lipopolysaccharide or live bacterial challenge. We will determine the site(s) of production and clearance of systemic SP-D and the transcriptional mechanisms that control production of systemic SP-D. We will identify the structural features of SP-D required for regulating systemic host defense cells. These studies will advance our understanding of the role of SP-D in systemic host defense. In addition, these studies will form the foundation for future translational studies to test SP-D in treatment of systemic infection and septic shock. The principle investigator of this grant has completed a Ph.D. in biochemistry, a clinical fellowship in neonatology, and is currently an Assistant Professor in the Section of Neonatology, Perinatal and Pulmonary Biology. Throughout his training, he has demonstrated repeated commitment to a career in scientific research. The experiments and training outlined in this grant will significantly broaden the skills and knowledge of the principle investigator and facilitate his development into an independent clinical scientist.