New Therapeutic Approach for Ricin-Induced Lung Injury

蓖麻毒素引起的肺损伤的新治疗方法

• 批准号: 7150220
• 负责人: KAM-MENG TCHOU-WONG
• 金额: $ 21.18万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150220
• 关键词: lung; lung injury; model; oligonucleotides; toxin

DESCRIPTION (provided by applicant): The increasing threat of bioterrorism worldwide has escalated the demand for the development of therapeutics for toxins that can be used as biological weapons. Ricin is a natural product of the castor bean (Ricinus communis) and a Category B toxin. It is a ribosome-inactivating protein that has the potential of being used as a biological weapon because of its heat stability, worldwide availability, ease in production and can be disseminated as an aerosol, a likely route that terrorists may use. When inhaled as a respirable aerosol, it causes irreversible pathological changes in the respiratory tract resulting in epithelial necrosis, pulmonary edema and alveolar flooding, and eventual death. The ricin toxin (RT) is a lectin consisting of two polypeptide chains linked by a disulfide bridge and cellular entry is required for toxicity. The B-chain (RTB) facilitates entry of the toxin into the cell and the A-chain (RTA) possesses RNA N-glycosidase activity that disables translation by depurinating a single adenine in the 28S eukaryotic ribosomal RNA (rRNA), thereby inducing ribotoxicity. In vitro selection has been used to generate RNA ligands (aptamers) specific for the catalytic RTA. These RNA aptamers inhibited RTA depurination and protects against ricin ribotoxicity. We hypothesize that post-exposure treatment can be developed against ricin ribotoxicity by delivering these novel anti-RTA aptamers intracellularly to inhibit RTA activity and toxicity. To test our hypothesis, the following aims are proposed: (1) To test the efficacy of the polycation polyethylenimine (PEI) in facilitating cellular uptake of aptamers and protective effects against ricin cytotoxicity in cell culture models; (2) To ascertain the efficacy of PEI-aptamers in the protection against ricin-induced lung injury and lethality and characterize the uptake of PEI-aptamers in the lungs; and (3) To validate the efficacy of PEI-aptamers in an aerosolized ricin mouse model. Relevance to Public Health: Since there is currently no treatment for ricin toxicity, there is an urgent need to develop effective antidotes for ricin. Because ricin is an important bioterrorist threat, our long-term goal is generate anti-toxin regimen for human use to protect the civilian and military populations against the use of ricin in acts of terrorism or war.

描述（由申请人提供）：全世界生物恐怖主义的日益威胁升级了对可以用作生物武器的毒素治疗学的需求。 Ricin是Castor Bean（Ricinus Communis）和B类B毒素的天然产物。这是一种核糖体吸收蛋白，由于其热稳定性，全球可用性，生产易于生产，可以用作生物武器，并且可以作为气溶胶散布，这是恐怖分子可能会使用的途径。当被吸入作为可呼吸的气溶胶时，会导致呼吸道的不可逆病理变化，导致上皮坏死，肺水肿和肺泡洪水以及最终死亡。 ricin毒素（RT）是一种凝集素，由两个由二硫键连接的两个多肽链组成，毒性需要细胞进入。 B链（RTB）有助于将毒素进入细胞，而A链（RTA）具有RNA N-糖苷酶活性，通过在28S真核生物核糖体RNA（RRNA）中降低单个腺嘌呤来禁用翻译，从而诱发了布体毒性。体外选择已用于产生针对催化RTA的RNA配体（适体）。这些RNA适体抑制了RTA脱位并预防ricin核糖毒性。我们假设暴露后治疗可以通过在细胞内提供这些新型的抗RTA适体来抑制RTA活性和毒性，以针对Ricin核糖毒性产生。为了检验我们的假设，提出了以下目的：（1）测试聚阳离子多乙基亚胺（PEI）在促进适体的细胞摄取中的功效，并针对ricin细胞毒性在细胞培养模型中的保护作用； （2）确定Pei-Appamers在防御Ricin诱导的肺损伤和致死性的保护方面的功效，并表征了肺中Pei-Appamers的摄取； （3）验证Pei-Appamers在雾化的Ricin小鼠模型中的功效。与公共卫生相关：由于目前尚无治疗Ricin毒性的治疗方法，因此迫切需要为Ricin开发有效的解毒剂。由于里辛是重要的生物恐怖主义威胁，我们的长期目标是为人类使用抗毒素方案，以保护平民和军事人口免受恐怖主义或战争行为中的使用。