Development of Nanomedicines for Tuberculosis Treatment

1”项目总结： 2.”撒哈拉以南非洲，特别是南非，受到致命疾病负担的严重挑战， 3”传染病，包括结核病（TB）。南非是世界上结核病负担最重的国家 4”（占全球负担的22.5%）。此外，对现有药物具有耐药性的结核病正在增加。然而，在这方面， 5”在药物发现管道中，结核病的新药很少。此外，令人鼓舞的是， 6”在当今抗生素耐药性不断增加的时代，新药面临着真实的威胁， 临床使用后很快出现病原体耐药性;正如最近对贝达喹啉观察到的那样， 8”，其中在临床使用后2年检测到耐药性。增加多种药物的组合 9”阻力、全球人口密度和国际旅行迫切要求发展 10”结核病新疗法。在这个为期5年的指导K43奖，我打算调查一个新的 采用纳米颗粒激活先天免疫系统治疗结核病的11”治疗模式 12”（免疫疗法）。作为布法罗大学纳米医学的博士后研究员， 用免疫调节配体（β-葡聚糖）功能化的13”纳米颗粒，并证明这些纳米颗粒 14”纳米颗粒可以刺激TB宿主细胞，即巨噬细胞，以产生细胞因子和氧化还原酶。 已知对根除结核病病原体结核分枝杆菌至关重要的15”种 16”（M.tb）。在这个奖项下，我将确定这种细胞反应是否会导致结核分枝杆菌的死亡， 17”巨噬细胞和小鼠。这项研究将产生概念数据的证明，以促进这一发展。 18“新的治疗方式。我之前在纳米医学方面的训练主要集中在纳米颗粒的合成上 19、“如何定义它们”然而，我的职业目标是成为发展的领导者， 20”纳米药物用于治疗传染病。因此，我打算接受广泛的培训 21”在生物学和免疫学的传染病和药代动力学，也提高我的 22“领导能力”我将通过完成教学和实践培训来获得这些技能 23、学习与学习的关系我相信这些额外的技能将补充我目前的技能（在 24”纳米颗粒合成），装备我合理设计纳米药物，并有效地与 25“传染病医学专家在我的职业生涯。我的导师团队由 26名结核病生物学、免疫学和纳米技术研究人员（南非导师）和药物 27”开发（美国导师）。我也将利用生物安全3级设施等稀缺资源 28”作为南非和美国机构的优秀教学和研究环境， 29”顺利完成我的培训和研究目标。 30” 31”

1" Project Summary: 2" Sub-Saharan Africa, in particular South Africa is disproportionately challenged by a burden of deadly 3" infectious diseases including tuberculosis (TB). South Africa has the highest burden of TB in the world 4" (22.5% of the global burden). Furthermore, TB that is resistant to existing drugs is on the rise. However, 5" there are very few new drugs for TB in the drug discovery pipeline. Further, it is not encouraging to note 6" that in the current era of increasing antimicrobial resistance, new drugs are faced with a real threat of 7" pathogen resistance emerging soon after clinical use; as was recently observed with bedaquiline, 8" whereby resistance was detected 2 years after clinical use. The combination of increasing multidrug 9" resistance, global population density and international travel urgently calls for the development of 10" novel therapeutics for TB. Under this 5-year mentored K43 award, I intend to investigate a new 11" treatment modality that employs nanoparticles to activate the innate immune system for treatment of TB 12" (immuno-therapy). As a Postdoctoral fellow in nanomedicine at the University at Buffalo, we synthesized 13" nanoparticles functionalized with an immune modulating ligand (β-glucan), and demonstrated that these 14" nanoparticles could stimulate the TB host cells, i.e. macrophages, to produce cytokines and oxidative 15" species known to be critical to the eradication of the TB causative organism Mycobacterium tuberculosis 16" (M.tb). Under this award, I will determine whether this cellular response leads to death of M.tb in 17" macrophages and mice. This study will generate proof of concept data towards the development of this 18" new treatment modality. My prior training in nanomedicine was focused on the synthesis of nanoparticles 19" and how to characterize them. However, my career objective is to be a leader in the development of 20" nanomedicines for the treatment of infectious diseases. Therefore, I intend to undergo extensive training 21" in the biology and immunology of infectious diseases and pharmacokinetics, and to also improve my 22" research leadership skills. I will gain these skills through completing didactic and hands-on training 23" courses and group learning. I believe these additional skills will complement my current skills (in 24" nanoparticle synthesis), to equip me to rationally design nanomedicines and effectively collaborate with 25" infectious disease medical experts throughout my career. My mentorship team comprises established 26" researchers in TB biology and immunology and nanotechnology (South Africa mentors) and drug 27" development (US mentor). I will leverage the scarce resources such as biosafety level 3 facilities as well 28" as the excellent teaching and research environment at institutions in South Africa and the US, to 29" successfully complete my training and research goals. 30" 31"