Exploiting a Bacterial Nano-Syringe for Protein Therapeutics

描述（由申请人提供）：纳米技术的巨大前景是开发用于无数用途的“分子机器”，特别是在生物医学中。正在进行广泛的努力，从各种元素和第一原理设计和生产这样的机器。我们建议采取一种“逆向工程”的方法来解决这个问题，利用一种在微生物世界中进化的分子机器，一种被称为“分子注射器”的细菌蛋白质注射系统。这种装置在致病菌中进化，可以精确地将蛋白质毒素输送到人体细胞中，因此可以作为“纳米注射器”，将能量转化为蛋白质注射的工作。我们计划使用这种注射装置向患病细胞中输送功能性真核蛋白质，这些蛋白质在疾病中已经突变或以其他方式变得无功能，以及可能抑制功能障碍蛋白质作用的蛋白质和肽。实例包括将功能性肿瘤抑制因子或促凋亡多肽恢复到转化的细胞系中，注射在遗传性疾病中突变的酶，以及添加转录抑制剂以实现其表达导致病理的某些基因的期望关闭。如果这些目标得以实现，我们将学会利用一种惊人的细菌纳米机器用于生物医学应用，为治疗潜在的广泛疾病提供一种新的强大工具。 项目叙述：我们提出调整细菌蛋白质注射系统以精确地将蛋白质和肽治疗剂递送到患病的人类细胞中。实例包括将功能性肿瘤抑制剂或促凋亡多肽恢复到转化的细胞系中，注射在遗传性疾病中突变的酶，以及添加转录抑制剂以实现其表达导致病理的某些基因中的期望关闭。如果这些目标得以实现，我们将学会利用这种惊人的细菌纳米机器进行生物医学应用，为治疗潜在的广泛疾病提供一种新的强大工具。

DESCRIPTION (provided by applicant): The great promise of nanotechnology is the development of "molecular machines" for a myriad of uses, and especially within biomedicine. Extensive efforts are underway to design and produce such machines from a variety of elements and first principles. We propose to take a "reverse-engineering" approach to this problem by exploiting a molecular machine that has evolved within the microbial world, a bacterial protein injection system called the "molecular syringe." This device has evolved in pathogenic bacteria to precisely deliver protein toxins into human cells, and therefore functions as a "nano-syringe," converting energy into the work of protein injection. We plan to use this injection device to deliver into diseased cells functional versions of eukaryotic proteins that have been mutated or otherwise rendered non-functional in the illness, as well as proteins and peptides that may inhibit the action of malfunctioning proteins. Examples include restoring functional tumor suppressors or pro-apoptotic polypeptides into transformed lines, injecting enzymes mutated in inherited diseases, and adding inhibitors of transcription to achieve a desired shut down in certain genes whose expression leads to pathology. Should these goals be realized, we will have learned to harness an amazing bacterial nano-machine for biomedical applications, providing a new and powerful tool for treating a potentially broad range of diseases. Project Narrative: We propose to adapt a bacterial protein injection system to precisely deliver protein and peptide therapeutics into diseased human cells Examples include restoring functional tumor suppressors or pro-apoptotic polypeptides into transformed lines, injecting enzymes mutated in inherited diseases, and adding inhibitors of transcription to achieve a desired shut down in certain genes whose expression leads to pathology. Should these goals be realized, we will have learned to harness this amazing bacterial nano- machine for biomedical applications, providing a new and powerful tool for treating a potentially broad range of diseases.