Proteomics and metabolomics systems analysis of envenomation by Bothrops snakes and antivenom effects using a murine model

动物毒液包括许多毒素，它们协同作用，破坏猎物生物体高度稳定的体内平衡系统。另一方面，猎物生物体积极对抗毒液蛰入现象的每一步，这表现出复杂的动力学，涉及分子、细胞、组织和生物体水平的重要变化。研究毒液和毒液蛰入的挑战包括两个障碍：第一，分析，分离和化学表征天然毒液中的各种毒素分子;第二，揭示毒液蛰入动力学的分子机制，包括从局部细胞和组织到整个生物体的全身反应。在以前的作品中，组学风格的调查，个别蛇毒金属蛋白酶（SVMP）的活动对复杂的生物系统允许评价的几个方面的病理学的蛇envenomation，以及在体内的影响引起的SVMP。在此背景下，本项目的总体目标是通过应用蛋白质组学和代谢组学方法探索Bothrops jararaca毒液在小鼠肌肉、血清、肾脏、肺和肝脏中的体内效应，扩展哺乳动物宿主对复杂毒素而不是单个组分的反应的系统分析。考虑到世界范围内蛇咬伤死亡和残疾的负担（世卫组织认为这是一种热带被忽视的疾病）以及抗蛇毒血清在治疗中的关键作用，还将评价抗虫抗蛇毒血清对全身毒液效应的影响。

Animal venoms comprise many toxins that act in concert to break apart the highly robust homeostatic systems of prey organisms. On the other hand, prey organisms actively antagonize each step of the envenomation phenomenon, which displays a complex kinetics involving important changes at molecular, cell, tissue and organism levels. The challenges for studying venoms and envenomation comprehend two hurdles: first, to analyze, isolate and chemically characterize the variety of toxin molecules in natural venoms; second, to uncover molecular mechanisms underlying the dynamics of envenomation, which includes systemic responses progressing from local cells and tissues up to the entire organism. In previous works, omics-style investigation of individual snake venom metalloproteinases (SVMP) activities on complex biological systems has allowed for the evaluation of several aspects of the pathology of the snake envenomation, as well as the in vivo effects triggered by SVMPs. In this context, the general aim of this project is expand the systems analysis of mammalian host response to complex toxins rather than individual components, by applying proteomics and metabolomics approaches to explore the in vivo effects of Bothrops jararaca venom in the muscle, serum, kidneys, lungs and liver of mice. Considering the worldwide burden of snakebite death and disability, which is recognized by the WHO as a tropical neglected disease, and the crucial role of antivenom in its treatment, the impact of anti-bothropic antivenom in the systemic venom effects will also be evaluated.