Targeted Killing of Bacteria in Communities

社区细菌定向杀灭

基本信息

批准号：
8757385
负责人：
Michiko E. Taga
金额：
$ 230.23万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The composition of microorganisms that reside in the human intestine (gut microbiota) has a profound impact on health. Recent work has shown links between the gut microbiota and conditions such as inflammatory bowel disease, obesity, and drug metabolism. There is great interest in harnessing this knowledge to develop methods of manipulating the gut microbiota as a new way to treat diseases associated with an improper composition of microbes. However, we are limited by our understanding of what manipulations of the community would promote better health because tools to address these questions are lacking. Despite considerable advances in elucidating the relationships between the microbiota and health, the challenge of understanding the contributions of individual bacteria cannot be fully addressed by current technologies. The goal of the proposed research is to address this challenge by developing a novel strategy that would allow the selective elimination of specific bacterial taxa from a community. The approach involves engineering broad host range phages to deliver an endonuclease that selectively cleaves a DNA sequence unique to the genome of the target bacterium, leading to cell death. The effectiveness and specificity of this targeted killing mechanism will be tested and refined in the model bacterium Escherichia coli and in cultured bacteria from the human gut. The germ-free mouse system colonized with bacteria from the human gut will be used as a model to test hypotheses about the functions of specific bacteria in the community. The development of a new technology to eliminate individual members of a microbial community could have profound impacts on the treatment of diseases associated with an imbalance of microbes, as well as those caused by a specific bacterial agent. Furthermore, this strategy could be widely applicable to the study of fundamental aspects of microbial communities.

描述（由申请人提供）：驻留在人类肠道（肠道微生物群）中的微生物的组成对健康具有深远的影响。最近的工作显示了肠道菌群与炎症性肠病，肥胖症和药物代谢等疾病之间的联系。利用这一知识来开发操纵肠道微生物群的方法非常感兴趣，以此作为治疗与微生物不当组成相关的疾病的一种新方法。但是，我们受到对社区的操纵的理解的限制，因为缺乏解决这些问题的工具。尽管在阐明微生物群与健康之间的关系方面取得了长足的进步，但当前技术无法完全解决个人细菌的贡献的挑战。拟议的研究的目的是通过制定一种新的策略来应对这一挑战，该策略将允许从社区中选择性消除特定的细菌分类单元。该方法涉及工程广泛的宿主范围噬菌体，以提供核酸内切酶，该核酸酶有选择地切割目标细菌基因组独有的DNA序列，从而导致细胞死亡。该靶向杀戮机制的有效性和特异性将在模型细菌大肠杆菌和人类肠道培养的细菌中进行测试和完善。从人类肠道中定居的细菌的无菌小鼠系统将用作模型，以测试有关社区特定细菌功能的假设。消除微生物群落个体成员的新技术的发展可能会对与微生物不平衡以及特定细菌剂引起的疾病的治疗产生深远的影响。此外，该策略可能广泛适用于研究微生物群落的基本方面。