Fighting Chagas Disease by genetic manipulation of nutrient pathways in Trypanosoma cruzi

该项目的目的是为治疗由克氏锥虫引起的恰加斯病寻找新的分子靶点。约有1亿人面临这种疾病的风险，每年约有12000人死于这种疾病。这种疾病在南美洲和中美洲最为流行，在那里，被俗称为“接吻虫”的昆虫充当媒介，将寄生虫传播给人类。由于迁徙，这种疾病正在向西方国家传播，因此正在成为一个全球卫生问题。感染克鲁兹病毒会导致致命的器官损伤，最常见的是心脏受到影响。目前的药物有严重副作用的风险，需要长时间的治疗，但不能保证治愈。为了指导更安全、更有效的治疗方法的开发，我希望识别和描述这种寄生虫在宿主内生存所需的关键分子途径。通过使用一种新的基因编辑工具箱，我们希望确定克氏锥虫用来从宿主获得营养(特别是维生素/矿物质)的蛋白质，以满足自身的新陈代谢需求。所涉及的工作将是定量的，包括基于计算生物信息学的分析以确定候选基因，以及用于突变筛选的高通量细胞分析。任何在细胞分析中显示出希望的基因都将在体内进行研究，以观察对整个生物体生理的影响。这项研究不仅具有潜在的医学可译性，而且是跨学科的，因为化学和细胞体外技术将与实时荧光成像和体内研究相结合。改造后的寄生虫将在少数小鼠身上进行监测，以观察组织迁移特征、负担和感染进展。此外，体外成像将用于观察宿主对修改的寄生虫的反应，并检查寄生虫在不同组织中的趋向性、存活和复制。为了更好地了解我的项目背景，我正在学习流行病学模块，这将拓宽我的跨学科知识库和技能集。通过参加定期研讨会，我从LSHTM和全国各地的大学正在进行的不同领域的研究中学习，这再次向我介绍了一系列方法和多个科学领域。随着我在博士学位上的进步，并确定对我的项目和职业发展有利的进一步技能，我将尽可能进行进一步的培训。

The aim of this project is to discover new molecular targets for the treatment of Chagas disease, caused by the parasitic agent Trypanosoma cruzi (T. cruzi). Approximately 100 million people are at risk of this affliction, which is responsible for around 12 000 deaths per year. The disease is most prevalent throughout South and Central America where insects known colloquially as 'kissing bugs' act as vectors and pass the parasites on to humans. Due to migration, the disease is spreading to Western countries and is therefore becoming a Global health issue. Infection with T cruzi can result in fatal organ damage, with the heart being most commonly affected. Current medications carry the risk of severe side effects and require long courses of treatment without guaranteeing cure. To direct the development of safer and more effective therapies, I hope to identify and characterise critical molecular pathways that the parasite requires to survive within its host. By using a novel gene-editing toolkit, we hope to identify proteins that T. cruzi uses to obtain nutrients (particularly vitamins/minerals) from the host to satisfy its own metabolic needs. The work involved will be quantitative, including computational bioinformatics-based analyses to identify candidate genes and high throughput cellular assays for mutant screening. Any genes that show promise in cellular assays will be studied in vivo to look at effects on the whole organism physiology. As well as being potentially medically translatable, the study is interdisciplinary, since chemical and cellular invitro techniques will be combined with live fluorescence imaging and in vivo studies. The modified parasites will be monitored in small numbers of mice to observe tissue migration characteristics, burden and progression of the infection. Furthermore, ex vivo imaging will be used to look at host responses to modified parasites and to examine parasite tropism, survival and replication in different organs.To better understand the context of my project, I am taking a module in epidemiology, which will broaden my inter-disciplinary knowledge base and skill-set. By attending regular seminars, I am learning from varying fields of research being undertaken at LSHTM and at universities across the country, which again introduces me to a range of methodology and to multiple areas of science. As I progress in this PhD and identify further skills which will benefit my project and career development, I will undertake further training as available.