Antimicrobial Gene Therapy

抗菌基因治疗

基本信息

批准号：
6623041
负责人：
GEORGE T.J HUANG
金额：
$ 15.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-15 至 2005-04-30
项目状态：
已结题

项目摘要

DESCRIPTION: Increasing resistance to conventional antibiotics has focused attention on alternative anti-infectious therapies. Antimicrobial peptides are promising new agents that have a low susceptibility to microbial resistance mechanisms. Unlike conventional antibiotics, antimicrobial peptides are encoded by single genes and can be introduced into infected tissues by gene therapy approaches. The ultimate goal of this study is to introduce antimicrobial peptide genes into explanted human cells, and to use these augmented cells to enhance host defense mechanisms against infection. The immediate goal is to develop a model system, in which the human-Beta-defensin-2 (HBD-2) gene will be expressed in HBD-2 negative cells; its antimicrobial effect will be tested in vitro and in vivo. The HBD-2 gene was chosen because, unlike most known defensins, it does not require tissue-specific processing. A retrovirus carrying the HBD-2 gene has permitted successful transduction of mouse fibroblast NIH/3T3 cells to secrete functional antimicrobial peptides in vitro. Additionally, successful transduction of various other cell types to secrete HBD-2 has been accomplished. While antibacterial activity of HBD-2 in vitro has been clearly demonstrated, limited information is available regarding HBD-2 function in vivo. Using a novel approach, there are plans to test whether secreted HBD-2 is functional in vivo. The central hypothesis is that this antimicrobial gene therapy is effective in enhancing host innate immunity against infection. One short-term objective is to test whether the transduced cells will defend against infection in vivo using mouse models. The Specific Aims include: 1) to determine the temporal expression and the antimicrobial effects of HBD-2 in transplanted cells in vivo in a mouse model. This Aim will utilize SCID mice to grow HBD-2 expressing tumors which model will allow quantitative measurement of the antimicrobial effect of HBD-2 in vivo. 2) To establish a tissue-engineered wound healing model to test antimicrobial gene therapy in mice. This Aim will establish a model that simulates a clinical situation for testing the application of this antimicrobial gene therapy approach. Successful completion of these Aims will be the first step in establishing in vivo animal study models to explore the future applicability of antimicrobial gene therapy. The proposed approach is intended to provide potential benefit in clinical applications in three ways: 1) transplanted antimicrobial secreting cells can be used in wounded, engineered or infected tissues to prevent and/or fight against infections; 2) these cells may reduce the need for conventional antibiotics; and 3) these cells may provide long-term augmentation of the innate immune system for immunocompromised patients.

描述：增加对常规抗生素的耐药性已集中注意替代性抗感染疗法。抗菌肽是有希望的新代理，对微生物抗性的敏感性较低机制。与常规抗生素不同，抗菌肽是编码的通过单个基因，可以通过基因治疗引入感染组织方法。这项研究的最终目标是引入抗菌剂肽基因进入外植的人类细胞，并使用这些增强细胞增强对感染的宿主防御机制。直接目标是开发一个模型系统，其中人β-防御素-2（HBD-2）基因将是在HBD-2阴性细胞中表达；它的抗菌作用将在体内和体内。选择HBD-2基因是因为，与最著名的防御素，它不需要组织特异性加工。逆转录病毒携带HBD-2基因已成功转导小鼠成纤维细胞NIH/3T3细胞在体外分泌功能性抗菌肽。此外，成功转导其他各种细胞类型以分泌 HBD-2已完成。而HBD-2体外HBD-2的抗菌活性已已清楚地证明，有关HBD-2的信息有限在体内功能。使用一种新颖的方法，有计划测试是否分泌的HBD-2在体内功能性。中心假设是抗菌基因疗法有效增强宿主先天免疫力反对感染。一个短期目标是测试转导的细胞将使用小鼠模型防御体内感染。具体目的包括：1）确定时间表达和抗菌剂 HBD-2在小鼠模型中体内移植细胞中的影响。这个目标利用SCID小鼠生长HBD-2表达肿瘤，这些模型将允许 HBD-2体内HBD-2的抗菌作用的定量测量。 2）到建立组织设计的伤口愈合模型以测试抗菌基因小鼠的治疗。这个目标将建立模拟临床的模型测试这种抗菌基因疗法应用的情况方法。成功完成这些目标将是建立的第一步体内动物研究模型，以探索抗菌剂的未来适用性基因疗法。拟议的方法旨在在以三种方式进行临床应用：1）移植的抗菌分泌细胞可用于受伤，工程或感染的组织，以预防和/或对抗感染； 2）这些细胞可能会减少常规的需求抗生素； 3）这些细胞可以长期增强免疫功能低下患者的先天免疫系统。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Capacity of human beta-defensin expression in gene-transduced and cytokine-induced cells.

基因转导和细胞因子诱导的细胞中人β-防御素表达的能力。

DOI：
10.1016/j.bbrc.2005.11.020
发表时间：
2006
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Yin,Chunyi;Dang,HoaN;Zhang,Hai-Bo;Gazor,Farzad;Kim,Daniel;Sorensen,OleE;Huang,GeorgeT-J
通讯作者：
Huang,GeorgeT-J

Apical Cyst Theory: a Missing Link.