Animal Models Core

动物模型核心

基本信息

批准号：
10089395
负责人：
Randall J Basaraba
金额：
$ 32.43万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2022-01-31
项目状态：
已结题

项目摘要

The Animal Models Core (D) is located within the Mycobacteriology Laboratory on the campus of Colorado State University. The Animal Infection Core is multidisciplinary with the expertise, personnel and facilities to model Mtb infection in guinea pigs with drug susceptible and resistant human clinical isolates as well as laboratory Mtb strains with targeted gene mutations. Our laboratory is also experienced and well equipped to model Mtb infection in guinea pigs with concurrent non-communicable diseases that are known TB risk factors in humans. Relevant to this proposal, we have developed the first ever model of Mtb infection in guinea pigs with diet-induced insulin resistance and type 2 diabetes that accurately mimics the comorbidity of tuberculosis and emerging noncommunicable diseases. In addition, we have designed and validated novel strategies to quantify pulmonary and extra-pulmonary tuberculosis disease burden in guinea pigs in response to experimental aerosol infection with drug susceptible and multi-drug resistant strains of Mycobacterium tuberculosis. We have recently characterized the profound alterations in systemic and cellular metabolism in response to Mycobacterium tuberculosis infection alone and demonstrated how preexisting alterations in host metabolism influences host susceptibility and in vivo disease progression. The Animal Models Core will parallel human cohort studies to 1) identify host metabolic determinants of tuberculosis disease control and progression and 2) use metabolomics to discover bacterial determinates of drug resistance and the discovery of host- and pathogen-derived biomarkers for tuberculosis diagnosis. Using the guinea pig model to study altered host metabolism associated with Mycobacterium tuberculosis infection has not only improved our understanding of the host-pathogen interaction but has identified potentially important therapeutic strategies that can be used as adjunct therapy in combination with conventional antimicrobial drug therapy. To fully exploit this model, the substantial existing core capabilities will be expanded to discover and validate additional biomarkers of altered host metabolism in guinea pigs infected with drug susceptible and drug resistant Mycobacterium tuberculosis.

动物模型核心 (D) 位于科罗拉多州校园的分枝杆菌学实验室内州立大学。动物感染核心是多学科的，拥有专业知识、人员和设施，豚鼠结核分枝杆菌感染模型与药物敏感和耐药人类临床分离株以及具有目标基因突变的实验室结核分枝杆菌菌株。我们的实验室也经验丰富且设备齐全患有已知结核病风险的并发非传染性疾病的豚鼠结核分枝杆菌感染模型人的因素。与该提案相关，我们开发了第一个 Mtb 感染模型患有饮食诱导的胰岛素抵抗和 2 型糖尿病的豚鼠准确地模拟了合并症结核病和新出现的非传染性疾病。此外，我们还设计并验证了新颖的量化豚鼠肺结核和肺外结核疾病负担的策略药物敏感和多重耐药菌株对实验性气溶胶感染的反应结核分枝杆菌。我们最近描述了系统性和细胞代谢对结核分枝杆菌感染的单独反应，并证明了如何宿主代谢中预先存在的改变会影响宿主的易感性和体内疾病进展。这动物模型核心将与人类队列研究并行，以 1) 确定宿主代谢决定因素结核病控制和进展，2) 使用代谢组学发现细菌决定因素耐药性以及发现宿主和病原体衍生的结核病诊断生物标志物。使用豚鼠模型研究与结核分枝杆菌相关的宿主代谢改变感染不仅提高了我们对宿主与病原体相互作用的理解，而且还确定了潜在重要的治疗策略，可作为辅助治疗与常规抗菌药物治疗。为了充分利用这种模式，现有的大量核心能力将扩展到发现和验证豚鼠宿主代谢改变的其他生物标志物感染耐药和耐药结核杆菌。