Systemic events in Clostridium difficile associated disease

艰难梭菌相关疾病的全身事件

• 批准号: 7899938
• 负责人: Jimmy D. Ballard
• 金额: $ 36.42万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899938
• 关键词: Animal Model; Antibiotic Resistance; Apoptosis; Apoptotic; Autopsy; Bacterial Toxins; Bacterial exotoxin; Blood; Blood Circulation; Cardiac; Cell Death; Clostridium difficile; Developed Countries; Direct Lytic Factors; Disease; Embryo; Event; Exotoxins; Exposure to; Gastrointestinal tract structure; Goals; Hamsters; Heart; In Vitro; Infection; Intoxication; Knowledge; Medical; Modeling; Mus; Organ; Organism; Pathogenesis; Patients; Reporting; Research Personnel; Series; Site; System; Systemic disease; Testing; Therapeutic; Tissues; Toxin; Virulence Factors; Work; Zebrafish; caspase-3; cytotoxic; design; immortalized cell; in vivo; inhibitor/antagonist; insight; interest; mortality; novel therapeutics; pathogen; prevent; programs; research study; resistant strain

DESCRIPTION (provided by applicant): Clostridium difficile initiates disease in the gastrointestinal tract and causes extracolonic damage by releasing toxins (TcdA and TcdB) into the bloodstream. Unfortunately, while much is known about the localized effects of these toxins at the site of infection, our understanding of the systemic effects of these toxins is limited. Recently, we reported that TcdB is a potent cardiotoxin, which alters cardiac function and damages the heart. However, cardiac damage could be completely alleviated by a caspase-3 inhibitor, in contrast to in vitro studies, which show only partial protection against TcdB using this inhibitor. These results suggest in vivo apoptotic cell death differs from that studied in vitro. The first series of experiments will elucidate the steps in apoptosis as they occur in vivo, in order to gain relevant insight into the activities of this toxin within the host. To date, almost nothing is known about the systemic effects of TcdA, although like TcdB, TcdA is a potent exotoxin. Using experimental approaches similar to those employed for TcdB, in the second aim of this study, we will elucidate the systemic effects of TcdA and determine this toxin may work in combination with TcdB. Finally, C. difficile associated disease is difficult to treat due to a high level of antibiotic resistant strains. In the final aim of this study we will explore several novel therapeutics designed to prevent systemic damage by TcdB and TcdA. The specific aims of this study are as follows: Specific Aim 1: The mechanism of TcdB-induced apoptosis in cardiac tissue will be determined. Specific Aim 2: The contribution of TcdA to systemic damage will be determined. Specific Aim 3: Candidate inhibitors of TcdA and TcdB will be evaluated for protection against systemic damage. Relevance: C. difficile associated disease is an increasing medical problem in many developed countries. Furthermore, there has been a concerning increase in mortality associated with this illness, yet little is known about steps in pathogenesis outside of the gastrointestinal tract. The studies proposed herein will provide important insight into systemic damage occurring in this disease, and test new candidate therapeutics.

描述（由申请人提供）：艰难梭状芽胞杆菌在胃肠道中引发疾病，并通过将毒素（TCDA和TCDB）释放到血液中，从而造成外部损害。不幸的是，尽管这些毒素在感染部位的局部效果知之甚少，但我们对这些毒素的系统性作用的理解是有限的。最近，我们报道了TCDB是​​一种有效的心脏毒素，可以改变心脏功能并损害心脏。然而，与体外研究相比，caspase-3抑制剂可以完全缓解心脏损伤，这仅显示使用该抑制剂对TCDB的部分保护。这些结果表明体内凋亡细胞死亡与体外研究的细胞死亡不同。第一个实验将在体内阐明凋亡的步骤，以便对宿主中这种毒素的活性进行相关的了解。 迄今为止，尽管像TCDB一样，TCDA是一种有效的外毒素，但几乎一无所知。使用与TCDB使用的实验方法，在这项研究的第二个目标中，我们将阐明TCDA的系统性效应，并确定这种毒素可以与TCDB结合使用。 最后，由于高水平的抗生素抗性菌株，艰难梭菌相关疾病很难治疗。在这项研究的最终目的中，我们将探索几种旨在防止TCDB和TCDA系统损害的新型治疗剂。这项研究的具体目的如下： 具体目标1：将确定TCDB诱导的心脏组织中凋亡的机制。 具体目的2：将确定TCDA对全身损害的贡献。 特定目标3：将评估TCDA和TCDB的候选抑制剂，以防止全身损害。 相关性：在许多发达国家，艰难梭菌相关疾病是越来越多的医疗问题。此外，与这种疾病相关的死亡率增加，但对胃肠道外的发病机理的步骤知之甚少。本文提出的研究将对这种疾病中发生的全身损害进行重要了解，并测试新的候选治疗剂。