Developing therapies to target the microbiota

开发针对微生物群的疗法

基本信息

批准号：
8755266
负责人：
June Louise Round
金额：
$ 223.5万
依托单位：
UNIVERSITY OF UTAH
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：
2014-09-01 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Mammals are home to a commensal microbial community referred to as the microbiota. Recent data has provided compelling evidence that microbial residents on mammals are crucial for proper development and health. Indeed, changes in intestinal microbial communities have been associated with inflammatory bowel disease (IBD), diabetes, allergies, obesity, multiple sclerosis and even autism. Recent research, including our own, has demonstrated that replacement of beneficial bacterial species or deletion of pathogenic microbes can protect and even cure diseases in animal model systems. While the presence of beneficial bacteria can prevent or cure disease the loss of these bacteria or the outgrowth of particular 'bad' commensal bacteria can induce disease. Therefore, it appears that maintaining the proper balance, or community structure, of commensal organisms is critical to health. This highlights the critical need to develop methodologies that allow for therapeutic manipulation of the microbiota. Current methodologies such as antibiotics or anti-microbials target large groups of bacteria and do not provide a sufficient level of specificity. Indeed, antibiotic use to clear a pathogen is well known to disrupt beneficial commensal communities, leading to permanent loss of particular members of the microbiota and creating niches for pathogens, a process referred to as dysbiosis. Moreover, greater antibiotic use has been correlated with increasing incidence of autoimmunity, likely because of disruptions to the beneficial organisms that we harbor. Thus, novel therapies to control bacterial populations and target specific organisms is sorely needed. This proposal will set forth experiments to better understand a numerically prominent member of our microbiota, our virobiota as a means to develop novel therapeutic strategies to manipulate health microbial communities. While the microbiota outnumbers our own cells by an order of magnitude, the virobiota is mainly composed of bacteriophages that outnumber the microbiota by estimated factor of 10. This means that bacteriophages represent one of the most abundant forms of foreign material on our bodies. While bacteriophages solely prey on bacteria as their hosts, an abundance of free phage has been found in both human and mouse mucus secretions, suggesting that phage has the capacity to influence immune system development on its own. Therefore, these studies have the potential to lay the foundation for the identification of novel ways to selectively get ri of pathogenic members of the microbiota that induce disease and exploring how these tiny bacterial predators may have shaped human evolution and health.

描述（由申请人提供）：哺乳动物是称为微生物群的共生微生物群落的家园。最近的数据提供了令人信服的证据，表明哺乳动物的微生物居民对于适当的发育和健康至关重要。实际上，肠道微生物群落的变化与炎症性肠病（IBD），糖尿病，过敏，肥胖，多发性硬化症甚至自闭症有关。最近的研究，包括我们自己的研究表明，替代有益细菌物种或致病性微生物的缺失可以保护甚至治愈动物模型系统中的疾病。尽管有益细菌的存在可以预防或治愈疾病，但这些细菌的丧失或特定“不良”共生细菌的生长会诱发疾病。因此，似乎保持共生生物的适当平衡或社区结构对健康至关重要。这凸显了开发允许对微生物群治疗操作的方法学的迫切需要。当前的方法（例如抗生素或抗微生物剂）靶向大量细菌，并且不能提供足够的特异性。实际上，众所周知，抗生素用于清除病原体是众所周知的，会破坏有益的共生群落，从而导致微生物群特定成员的永久丧失并为病原体创建壁ni，这一过程称为营养不良。此外，更大的抗生素使用与自身免疫的发生率的增加有关，这可能是由于我们携带的有益生物的中断。因此，迫切需要进行新的控制细菌群体和靶向特定生物的疗法。该建议将制定实验，以更好地了解我们的微生物群的数字杰出成员，即我们的Virobiota，作为开发新型治疗策略来操纵健康微生物群落的手段。虽然微生物群的数量级超过了我们自己的细胞，但virobiota主要由噬菌体组成，据估计的因子超过微生物群，这意味着噬菌体代表了我们身体上最丰富的异物之一。尽管噬菌体仅捕食细菌作为宿主，但在人和小鼠粘液分泌中都发现了大量的自由噬菌体，这表明噬菌体具有自身影响免疫系统发育的能力。因此，这些研究有可能为鉴定新的方法奠定基础，以选择性地获得诱导疾病并探索这些细菌捕食者如何塑造人类进化和健康的菌群的病原体成员。