Newton001 Proof-of concept screen to counteract Bothrops toxins targeting tissue cohesion

在巴西，动物中毒事故造成的相当大的人类发病率和死亡率造成了很高的公共卫生、经济和社会成本。蛇咬伤是一种主要的职业危害，农村现有的农业社区是这种情况的主要受害者。在巴西，每年有超过20，000起事故是由Bothrops物种造成的，相当于所有记录在案的蛇咬伤的90%。棘头蛇属毒液蛰入的特点是局部组织严重受损，包括出血、坏死和水肿，以及凝血系统紊乱。自20世纪20年代以来，抗蛇毒免疫疗法是世界卫生组织（WHO）批准的唯一有效的蛇咬伤治疗方法。然而，它有重要的局限性和副作用，包括无法防止蛇咬伤部位的局部损伤和一些患者的过敏性休克。因此，有一个未满足的临床需要，开发新的药理学疗法，可以抵消蛇毒和/或被用作coadjuvant治疗与anti-venoms.Understanding蛇毒如何接口与细胞事件重要的组织动态平衡是有用的，以通知新的治疗方法然而，envenomation的分子和细胞方面了解甚少。尽管巴西不同的实验室做出了广泛的努力，以确定特定毒素的生化特性及其在动物模型中的体内后果。牛顿基金会/CONFAP目前的研究伙伴关系的目的是（i）建立和优化筛选，以确定可能的治疗候选人，以促进对Bothrops毒液损伤的细胞反应，（ii）开发适合于剖析蛇毒液中毒机制的新技术。在毒液生物化学和细胞信号传导方面，这项建议将确定药物开发的线索，对治疗毒液蛰入病人具有重要的临床意义。

In Brazil, the considerable human morbidity and mortality caused by accidents with poisoning animals pose high public health, economical and societal costs. Snakebite is a major occupational hazard, and rural subsistent farming communities are the main sufferers from this condition. Bothrops species are responsible for more than 20,000 accidents per year in Brazil, corresponding to 90% of all recorded snakebites. Bothrops spp. envenomation is characterized by prominent local tissue damage, including haemorrhage, necrosis and oedema as well as disturbance in the blood coagulation system. Since 1920's, immunotherapy by anti-venoms is the only efficacious treatment for snakebites accidents approved by WHO (World Health Organization). Yet, it has important limitations and side-effects, including inability to prevent local damage at the snakebite site and anaphylatic shock in some patients. Thus, there is an unmet clinical need to develop novel pharmacological therapies that can counteract snake venoms and/or be used as coadjuvant therapy with anti-venoms.Understanding how the snake venom interfaces with cellular events important for tissue homeostasis is instrumental to inform novel therapies Yet, the molecular and cellular aspects of envenomation are poorly understood. This is in spite of extensive efforts from different labs in Brazil to characterise the biochemical properties of specific toxins and their in vivo consequences in animal models. The aim of the current Research Partnership from the Newton Fund/CONFAP is to (i) set up and optimise a screen to identify likely therapeutic candidates to facilitate cellular response to injury by Bothrops venom and (ii) develop novel techniques suitable to dissect mechanisms of snake envenomation.Driven by unique strengths of the co-applicants in venom biochemistry and cellular signalling, this proposal will identify leads for drug development with important clinical implications for treatment of envenomation patients.