Bio-Therapies for Cancer and Infectious Disease

癌症和传染病的生物疗法

• 批准号: 6559023
• 负责人: DAVID FITZGERALD
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559023
• 关键词: Pseudomonas; biotechnology; cystic fibrosis; disease /disorder model; epithelium; exotoxins; gene expression; immunoconjugates; laboratory mouse; laboratory rat; microarray technology; nonhuman therapy evaluation; substance P; vaccine development; vaccines

Pseudomonas exotoxin kills most cells and tissues. However, polarized epithelial cells are resistant to Pseudomonas exotoxin and in some circumstances to diphtheria toxin. The basis for this finding is currently being investigated. Toxins may take a novel pathway and transcytose across polarized cells rather than kill them. cDNA microarrays are being used to compare gene expression profiles in toxin resistant cells with those of toxin sensitive cells. Preliminary data indicate that resistance cannot be explained on the basis that polarized cells lack the expression of any known member of the toxin intracellular pathway. Novel candidate genes are being pursued. The administration of Pseudomonas exotoxin onto the airway epithelia of mice was used as a model system to follow the fate of toxin released by Pseudomonas aeruginosa during infection of CF patients. Results indicate that the toxin can cross to the serosal side of the epithelium and destroy cells of the spleen and liver as well as those in local lymph nodes. The delivery of a non-toxic version of the toxin to local lymph nodes and spleen may be a useful path for vaccine administration. Neurokinin receptors can function as surface targets for neuropeptide-toxin conjugates and this may lead to selective nerve cell ablation. Substance P-PE35 conjugates were administered into the lumbar region of the spinal column of rats. Eight days later, sections of spinal column of treated Vs non-treated animals were compared. In rats treated with SubP-PE35 all neurons staining for the NK1 receptor had been ablated. Despite this, rats appeared to act no different from their untreated litter mates. We are investigating the toxin's ability to act as a carrier for key pilin sequences. The PE-pilin protein is being developed as a candidate vaccine for cystic fibrosis.

假单胞菌异毒素杀死大多数细胞和组织。然而，极化上皮细胞对假单胞菌毒素具有抗性，在某些情况下对白喉毒素的白喉毒素具有抗性。目前正在研究这一发现的基础。毒素可能会采取新颖的途径和跨偏光细胞的跨环节，而不是杀死它们。 cDNA微阵列用于比较抗毒素敏感细胞中抗毒素细胞中的基因表达谱。初步数据表明，无法根据极化细胞缺乏毒素细胞内途径的任何已知成员的表达来解释抗性。正在追求新颖的候选基因。假单胞菌的假单胞菌毒素在小鼠的气道上皮上被用作模型系统，以遵循铜绿假单胞菌在CF患者感染期间释放的毒素命运。结果表明，毒素可以跨越上皮的浆膜侧，破坏脾脏和肝脏的细胞以及局部淋巴结中的细胞。将毒素的无毒版本传递到局部淋巴结和脾脏可能是疫苗给药的有用途径。神经激素受体可以充当神经肽毒素结合物的表面靶标，这可能导致选择性神经细胞消融。物质P-PE35结合物被施用到大鼠脊柱的腰部区域。八天后，比较了处理过的与未处理的动物的脊柱柱。在用Subp-Pe35处理的大鼠中，所有NK1受体的神经元染色都已消融。尽管如此，老鼠似乎与未经处理的垃圾伴侣没有什么不同。我们正在研究毒素充当关键PILIN序列的载体的能力。 PE-pilin蛋白正在作为囊性纤维化的候选疫苗开发。