Development of Nanomedicines for Tuberculosis Treatment

结核病治疗纳米药物的开发

• 批准号: 9892050
• 负责人: Admire Dube
• 金额: $ 7.62万
• 依托单位: UNIVERSITY OF THE WESTERN CAPE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-22 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892050
• 关键词: Africa; Africa South of the Sahara; Alveolar; Animal Model; Antimicrobial Resistance; Award; Biology; Buffaloes; Bypass; Cell model; Cells; Cessation of life; Chitosan; Clinical; Communicable Diseases; Competence; Complement; Data; Development; Drug Kinetics; Educational process of instructing; Ensure; Environment; Generations; Glucans; Glycolates; Goals; Histopathology; Human; Immune; Immune system; Immunology; Immunotherapy; Incubated; Individual; Infectious Disease Immunology; Inflammatory; Innate Immune System; Institution; International; Intravenous; Investigation; Kinetics; Leadership; Learning; Ligands; Liver; Lung; Measures; Medical; Mentors; Mentorship; Methods; Modality; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium tuberculosis; Nanotechnology; Nitrogen; Organism; Oxygen; Pharmaceutical Preparations; Pharmacology; Population Density; Postdoctoral Fellow; Production; Public Health; Radial; Reporting; Research; Research Personnel; Resistance; Resources; Rifampicin resistance; Rifampin; Scientist; Series; Serum; South Africa; Spleen; Surface; TNF gene; Time; Training; Travel; Tuberculosis; Universities; Work; antimicrobial; bactericide; base; beta-Glucans; biosafety level 3 facility; career; chemokine; cytokine; cytotoxicity; design; drug action; drug development; drug discovery; drug release kinetics; frontier; improved; infectious disease treatment; innovation; isoniazid; macrophage; microbial; mortality; nanomedicine; nanoparticle; novel therapeutics; pathogen; response; skills; synergism; tuberculosis drugs; tuberculosis treatment

Project Summary: Sub-Saharan Africa, in particular South Africa is disproportionately challenged by a burden of deadly infectious diseases including tuberculosis (TB). South Africa has the highest burden of TB in the world (22.5% of the global burden). Furthermore, TB that is resistant to existing drugs is on the rise. However, there are very few new drugs for TB in the drug discovery pipeline. Further, it is not encouraging to note that in the current era of increasing antimicrobial resistance, new drugs are faced with a real threat of pathogen resistance emerging soon after clinical use; as was recently observed with bedaquiline, whereby resistance was detected 2 years after clinical use. The combination of increasing multidrug resistance, global population density and international travel urgently calls for the development of novel therapeutics for TB. Under this 5-year mentored K43 award, I intend to investigate a new treatment modality that employs nanoparticles to activate the innate immune system for treatment of TB (immuno-therapy). As a Postdoctoral fellow in nanomedicine at the University at Buffalo, we synthesized nanoparticles functionalized with an immune modulating ligand (β-glucan), and demonstrated that these nanoparticles could stimulate the TB host cells, i.e. macrophages, to produce cytokines and oxidative species known to be critical to the eradication of the TB causative organism Mycobacterium tuberculosis (M.tb). Under this award, I will determine whether this cellular response leads to death of M.tb in macrophages and mice. This study will generate proof of concept data towards the development of this new treatment modality. My prior training in nanomedicine was focused on the synthesis of nanoparticles and how to characterize them. However, my career objective is to be a leader in the development of nanomedicines for the treatment of infectious diseases. Therefore, I intend to undergo extensive training in the biology and immunology of infectious diseases and pharmacokinetics, and to also improve my research leadership skills. I will gain these skills through completing didactic and hands-on training courses and group learning. I believe these additional skills will complement my current skills (in nanoparticle synthesis), to equip me to rationally design nanomedicines and effectively collaborate with infectious disease medical experts throughout my career. My mentorship team comprises established researchers in TB biology and immunology and nanotechnology (South Africa mentors) and drug development (US mentor). I will leverage the scarce resources such as biosafety level 3 facilities as well as the excellent teaching and research environment at institutions in South Africa and the US, to successfully complete my training and research goals.

项目总结： 撒哈拉以南非洲，特别是南非，面临着致命的 包括结核病(TB)在内的传染病。南非的结核病负担是世界上最高的 (全球负担的22.5%)。此外，对现有药物具有抗药性的结核病正在上升。然而， 在药物发现流水线中，治疗结核病的新药很少。此外，注意到以下情况并不令人鼓舞 在目前抗菌素耐药性不断增强的时代，新药面临着真正的威胁 临床使用后不久出现病原菌抗药性；就像最近用贝达奎兰观察到的那样， 从而在临床使用2年后检测到耐药性。不断增加的多药联用 阻力、全球人口密度和国际旅行迫切要求发展 结核病的新疗法。在这个为期5年的K43导师奖下，我打算调查一个新的 利用纳米粒子激活天然免疫系统治疗结核病的治疗模式 (免疫疗法)。作为布法罗大学纳米医学的博士后研究员，我们合成了 纳米颗粒具有免疫调节配体(β-葡聚糖)的功能，并证明了这些 纳米颗粒可以刺激结核宿主细胞，即巨噬细胞，产生细胞因子和氧化 已知对根除结核病致病微生物结核分枝杆菌至关重要的物种 (M.tb)。根据这项裁决，我将确定这种细胞反应是否导致结核分枝杆菌在 巨噬细胞和小鼠。这项研究将为这一发展提供概念验证数据 新的治疗方式。我之前在纳米医学方面的培训主要集中在纳米颗粒的合成上 以及如何描述它们。然而，我的职业目标是成为发展中的领导者 治疗传染病的纳米药物。因此，我打算接受广泛的培训 在传染病的生物学和免疫学以及药代动力学方面，也改善了我的 研究领导技能。我将通过完成授课和动手培训来获得这些技能 课程和小组学习。我相信这些额外的技能将补充我目前的技能(在 纳米粒子合成)，使我能够合理设计纳米药物并有效地与 在我的职业生涯中一直是传染病医学专家。我的导师团队由已建立的 结核病生物学、免疫学和纳米技术(南非导师)和药物研究人员 发展(美国导师)。我也会利用稀缺的资源，如生物安全三级设施 作为南非和美国院校良好的教学和研究环境， 圆满完成了我的培训和研究目标。