Hunting the PLUNCs, a novel innate immune family

描述（由申请人提供）：在这个申请中，我们介绍了一个新的分子家族，PLUNC蛋白家族。PLUNC代表腭、肺和鼻上皮克隆，首次在小鼠中命名。基因组调查预测，在人类中至少有9种这种蛋白质，在其他哺乳动物（如大鼠、小鼠和奶牛）中也发现了多种同源蛋白。它们都是小的分泌蛋白质。一些证据支持PLUNCs作为一个独立的哺乳动物基因家族在先天免疫中发挥作用。这些包括它们保守的基因组位点、相似的内含子-外显子结构、组织特异性表达模式和预测的蛋白质折叠。具体来说，plunc的三维结构类似于一种重要的免疫防御者BPI（杀菌/通透性增加蛋白）。BPI通过与脂多糖（LPS）结合来抑制身体对感染的反应，脂多糖是革兰氏阴性菌外壁的一种成分。BPI中和LPS，降低灾难性炎症反应的风险，包括感染性休克和死亡。鉴于PLUNC与BPI的相似性，我们提出了三个特定的目标来更多地了解这个鲜为人知但却多样化的哺乳动物蛋白家族：1)定位PLUNC基因在小鼠中的组织特异性表达，2)构建分泌多种PLUNC亚型的哺乳动物细胞系，以及3)测试这些分泌的蛋白是否可以结合LPS，将其从炎症级联反应中清除。综上所述，PLUNC蛋白代表了先天免疫研究和感染治疗的一个新的治疗靶点家族。

DESCRIPTION (provided by applicant): In this application we introduce a novel family of molecules, the PLUNC protein family. PLUNC stands for palate, lung and nasal epithelium clone, as first named in mice. Genomic surveys predict at least nine of these proteins in humans and multiple homologs have been identified in other mammals such as rats, mice and cows. All are small, secreted proteins. Several lines of evidence support the PLUNCs as a discrete mammalian gene family with a role in innate immunity. These include their conserved genomic locus, their similar intron-exon structure, their tissue-specific expression patterns and their predicted protein folds. Specifically, the three-dimensional structure of the PLUNCs is similar to that of an important immune defender, BPI (bactericidal/permeability-increasing protein). BPI dampens the body's response to infection by binding to lipopoylsaccharide (LPS), a component of the outer wall of Gram-negative bacteria. BPI neutralizes LPS and reduces the risk of catastrophic inflammatory responses, including septic shock and death. Given the similarity of PLUNCs to BPI, we propose three specific aims to understand more about this poorly known but diverse mammalian protein family: 1) locate the tissue-specific expression of PLUNC genes in mice, 2) construct mammalian cell lines that secrete multiple isoforms of PLUNC, and 3) test whether these secreted proteins can bind LPS, removing it from the inflammatory cascade. Taken together, the PLUNC proteins represent a novel family of therapeutic targets for the study of innate immunity and the treatment of infection.