Surfactant Protein D in Pulmonary and Systemic Host Defense

描述(由申请人提供)： 表面活性蛋白D(SP-D)是胶原蛋白家族中的一员。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还结合内毒素等炎性分子，并限制这些分子引起的炎性损害。由于其在肺免疫系统中的作用，SP-D正被开发为一种治疗剂，旨在限制肺部微生物的生长和由此导致的炎症损害。SP-D也存在于许多非肺脏部位，但肺外SP-D的来源和功能尚不清楚。我们的初步结果表明，SP-D也参与了系统的寄主防御。因此，这一应用试图检验SP-D在清除系统病原体和调节系统寄主防御中发挥作用的普遍假设。为了验证这一假说，我们将确定静脉注射SP-D是否能改善暴露在脂多糖或活细菌攻击下的小鼠的炎症、组织损伤和存活率。我们将确定系统性SP-D的产生和清除的位点(S)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在系统寄主防御中的作用的理解。此外，这些研究将为未来的翻译研究奠定基础，以测试SP-D在治疗全身感染和感染性休克中的作用。这笔赠款的首席研究员已经完成了生物化学博士学位，这是一项新生儿临床奖学金，目前是新生儿学、围产期和肺生物学部门的助理教授。在整个训练过程中，他一再表现出对科学研究事业的承诺。这笔赠款中概述的实验和培训将极大地拓宽首席研究员的技能和知识，并促进他发展成为一名独立的临床科学家。

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.