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

该项目的目的是发现治疗恰加斯病的新分子靶点，恰加斯病是由寄生虫克氏锥虫（T.克氏）引起的。大约有1亿人面临这种痛苦的风险，每年造成约1.2万人死亡。这种疾病在南美洲和中美洲最为普遍，在那里，俗称“接吻虫”的昆虫充当媒介，将寄生虫传播给人类。由于移民，这种疾病正在向西方国家蔓延，因此正在成为一个全球性的健康问题。感染克氏T型病毒可导致致命的器官损伤，最常见的是心脏。目前的药物有严重副作用的风险，需要长时间的治疗而不能保证治愈。为了指导更安全、更有效的治疗方法的发展，我希望确定和描述寄生虫在其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，我们希望鉴定出T. cruzi用来从宿主那里获取营养（特别是维生素/矿物质）以满足自身代谢需求的蛋白质。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，以确定候选基因和用于突变筛选的高通量细胞分析。任何在细胞分析中表现出希望的基因都将在体内进行研究，以观察其对整个生物体生理的影响。除了具有潜在的医学可翻译性外，这项研究是跨学科的，因为化学和细胞体外技术将与活体荧光成像和体内研究相结合。将在少量小鼠中监测改造后的寄生虫，观察感染的组织迁移特征、负担和进展。此外，体外成像将用于观察宿主对改良寄生虫的反应，并检查寄生虫在不同器官中的趋向性、存活和复制。为了更好地理解我的项目背景，我选修了流行病学的一个模块，这将拓宽我的跨学科知识基础和技能。通过参加定期研讨会，我从LSHTM和全国各地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的方法和多个科学领域。随着我在博士学位学习上的进步，并确定了对我的项目和职业发展有益的进一步技能，我将尽可能接受进一步的培训。

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.