Exploiting a Bacterial Nano-Syringe for Protein Therapeutics

描述(申请人提供)：纳米技术的巨大前景是开发出可用于多种用途的“分子机器”，尤其是在生物医学领域。目前正在进行广泛的努力，根据各种元素和基本原则来设计和生产这种机器。我们建议采用一种“逆向工程”的方法来解决这个问题，方法是利用微生物世界中进化出的一种分子机器，即一种被称为“分子注射器”的细菌蛋白质注射系统。这种装置已经在致病细菌中进化，能够准确地将蛋白质毒素输送到人类细胞中，因此起到了“纳米注射器”的作用，将能量转化为蛋白质注射的工作。我们计划使用这种注射设备将在疾病中突变或以其他方式变得不起作用的真核蛋白的功能版本，以及可能抑制故障蛋白作用的蛋白质和多肽，输送到患病细胞中。例如，将功能性肿瘤抑制因子或促凋亡多肽恢复到转化系中，向遗传性疾病中注入突变的酶，以及添加转录抑制剂以实现某些基因的理想关闭，这些基因的表达会导致病理。如果这些目标实现，我们将学会利用一种令人惊叹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。 项目简介：我们建议调整细菌蛋白注射系统，以将蛋白质和多肽疗法精确地输送到患病的人类细胞中。例如，将功能性肿瘤抑制因子或促凋亡多肽恢复到转化系中，注入在遗传病中突变的酶，以及添加转录抑制物以实现某些基因的理想关闭，这些基因的表达会导致病理。如果这些目标实现，我们将学会利用这种令人惊叹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。

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.