NOVEL DEFENSINS IN HUMAN EPITHELIAL TISSUE

尽管在预防和管理方面取得了许多重大进展， 传染病仍然占相当大的发病率和 死亡率。包括人类在内的哺乳动物防御的机制 针对微生物入侵的定义并不完全。防御素是 最近发现的富含半胱氨酸的阳离子多肽 几种哺乳动物吞噬细胞中的丰度。这些多肽 在一定程度上对非氧化性杀微生物活性负责 将这些细胞转化为微生物。四种防御素，都是从 来自颗粒的白细胞已知存在于人类中。在体外， 防御素对细菌、真菌和包膜具有很强的活性 病毒。最近在动物模型中的研究发现，此外 对于白细胞，上皮细胞也表达防御素相关的 分子。 该提案中提出的初步研究表明，有明确的证据表明 防御素基因在人类非造血组织中的新表达。 利用分子生物学方法，已经获得了强有力的数据。 这表明人类防御素家族比 目前受到赞赏，其中一些是新的。已发现的防御素 仅在上皮细胞中表达。的长期目标 本研究旨在明确上皮防御素在宿主中的作用 防守。 为实现这一目标，提出了以下实验：1)克隆和 鉴定与非造血防御素相对应的基因， 建立选定基因及其侧翼的核苷酸序列 序列，并确定这些基因的区域图谱 2)克隆和鉴定新基因的编码区 非造血者防御素及防御素相关肽S 组织；3)细胞定位和抗菌特性 新发现的防御素的性质；4)鉴定和 描述调节防御的顺式作用元件 表情。 上皮源性防御素很可能为粘膜表面配备 一种以前未被承认的防御能力，与其他 明确的抗菌防御措施。对这一问题的理解 人体上皮防御素的生理调节可能 最终导致内源性多肽的治疗调节 表达，并可能导致新的治疗方法的开发 抗菌肽。

Despite many significant advances in its prevention and management, infectious disease still accounts for considerable morbidity and mortality. The mechanisms by which mammals, including humans defend against microbial invasion are incompletely defined. Defensins are recently identified cysteine-rich, cationic peptides found in abundance in phagocytic leukocytes of several mammals. These peptides are responsible, in part, for the non-oxidative microbicidal activity of these cells toward microorganisms. Four defensins, all derived from granular leukocytes are known to exist in humans. In vitro, defensins have potent activity against bacteria, fungi and enveloped viruses. Recent studies in animal models have found that in addition to leukocytes, epithelial cells also express defensin-related molecules. Preliminary studies presented in this proposal show clear evidence of novel defensin gene expression in non-hematopoietic tissue of humans. Using a molecular biological approach, strong data have been obtained indicating that the family of human defensins is more diverse than currently appreciated, and some of these newly. discovered defensins are expressed exclusively in epithelial cells. The long range goal of this research is to define the role of epithelial defensins in host defense. Toward this goal the following experiments are proposed: 1) Clone and characterize genes corresponding to the non-hematopoietic defensins, establish the nucleotide sequence of selected genes and their flanking sequences, and determine a regional map of these genes which appear to be clustered; 2) Clone and characterize the cDNA encoding novel defensins and defensin-related peptide(s) from non-hematopoietic human tissues; 3) Characterize the cellular localization and antimicrobial properties of the newly discovered defensins; 4) Identify and characterize the cis-acting elements which regulate defensin expression. Epithelial-derived defensins are likely to equip mucosa] surfaces with a previously unrecognized defensive capability that complements other well-defined antimicrobial defenses. The understanding of the physiological regulation of epithelial defensins in humans may ultimately lead to therapeutic modulation of endogenous peptide expression, and may lead to the development of novel therapeutic antimicrobial peptides.