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， mortality. 包括人类在内的哺乳动物的防御机制 对微生物入侵的影响还没有完全确定。 防御素是 最近发现的富含半胱氨酸的阳离子肽， 在几种哺乳动物的吞噬性白细胞中的丰度。 这些肽 在某种程度上， 这些细胞对微生物。 四种防御素， 已知存在于人类中。 在体外， 防御素具有有效的抗细菌、真菌和包膜的活性， 病毒。 最近在动物模型中的研究发现， 与白细胞相比，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， 新的防御素基因在人类非造血组织中的表达。 使用分子生物学方法， 这表明人类防御素家族比人类防御素家族更多样化。 目前，其中一些是新的。发现防御素 仅在上皮细胞中表达。 长期目标是 本研究旨在明确上皮防御素在宿主细胞中的作用， 防御 为实现这一目标，提出了以下实验：1）克隆和 表征对应于非造血防御素的基因， 确定所选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，这些基因似乎 2）克隆和鉴定编码新的 来自非造血系统人的防御素和防御素相关肽 组织; 3）表征细胞定位和抗微生物 新发现的防御素的性质; 4）鉴定和 表征调节防御素的顺式作用元件 表情 上皮来源的防御素可能使粘膜表面具有 一种以前未被认识到的防御能力， 明确的抗菌防御。 的理解 人的上皮防御素的生理调节可能 最终导致内源性肽治疗调节 表达，并可能导致新的治疗方法的发展， 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.