Development of a novel therapeutic to treat snakebite induced necrosis in sub-Saharan Africa

拟议的博士学位是为了在撒哈拉以南非洲开发一种针对蛇毒引起的坏死的有针对性的治疗方法。目前，也是唯一一种治疗蛇咬伤的方法(从用毒液过度免疫的马/羊身上提取的抗蛇毒-IgG/S)，虽然在逆转蛇毒的潜在致命全身影响方面有效，但在否定/逆转组织坏死效应方面无效。据全球估计，每年有40万人因毒液引起的坏死而毁容或致残。仅在撒哈拉以南非洲，估计每年就有14000例截肢直接可归因于蛇咬伤。然而，关于单个毒液成分是如何导致坏死的，人们知之甚少。虽然有已发表的文献表明哪些蛋白质被认为是导致坏死的主要原因，但仅关注这一病理方面的工作很少，特别是在撒哈拉以南非洲物种中。开发一种治疗毒液诱导的坏死的疗法是一项紧迫而紧迫的临床需求，更好地了解潜在的过程将是非常宝贵的。撒哈拉以南地区的三个关键物种(根据地理分布、被人类叮咬的频率和造成的坏死严重程度)已被确定为Echis ocel/atus、Bitis arietans和Naja nigricollis。来自这三个物种的毒素和单个毒素将构成整个PhD的基础。PHD的范围包括识别所有这三种毒素中的坏死诱导毒素(NIT)，检查它们在体外和体内模型中的影响，以及设计(和测试)NIT靶向治疗药物。这些也是利用相同的方法进一步扩大PHD以包括高度导致坏死的亚洲物种的潜力，如平纹大熊猫和Ca//ose/Asma红口藻。博士学位的第一年将致力于从撒哈拉以南非洲的三种目标毒液中识别和隔离这些蚊虫。为了实现这些目标，将应用几种不同的方法：生物信息学、重组蛋白表达、层析和生物活性分析。这些不同的技术中的每一种都构成了它自己不同的工作阶段。

The proposed PhD is to develop a targeted therapeutic against snake venom-induced necrosis in sub-Saharan Africa. The current, and only, treatment for snakebite (antivenom - lgG from horses/sheep hyperimmunised with venom/s)), while effective at reversing the potentially lethal systemic effects of envenoming is ineffective at negating/reversing the tissue-necrotic effects. The global estimates are that 400'000 individuals are left disfigured or disabled every year due to venom-induced necrosis. In sub-Saharan Africa alone there are an estimated 14'000 amputations each year directly attributable to snakebite. However, little is understood about how individual venom components act to cause necrosis. Whilst there is published literature indicating which proteins are thought to be integral to the causation of necrosis, little has been done focusing on this pathology alone, especially in sub-Saharan African species. The development of a therapy to treat venom-induced necrosis is an urgent and compelling clinical need, and a better understanding of the underlying processes will be invaluable. Three key sub- Saharan species (based on geographical distribution, frequency of human bites and severity of necrosis caused) have been identified as Echis ocel/atus, Bitis arietans and Naja nigricollis. The venoms, and individual toxins, from these three species will form the basis of the entire PhD.The scope of the PhD covers the identification of necrosis-inducing toxins (NITs) within all three of these venoms, examining their effects in ex vivo and in vivo models, and designing (and testing) NIT targeting therapeutics. These is also the potential in expand the PhD further to include highly necrosis-inducing Asian species, such as Daboia russelii and Ca//ose/asma rhodostoma, using the same approaches. The first year of the PhD will be dedicated to the identification and isolation of these NITs from the three sub-Saharan Africa target venoms. In order to achieve these aims several different methodologies will be applied; bioinformatics, recombinant protein expression, chromatography and bioactivity assays. Each of these different techniques constitutes its own distinct phase of work.