Genomic analysis of malaria resistance

疟疾耐药性的基因组分析

• 批准号: G0600230/1
• 负责人: Dominic Kwiatkowski
• 金额: $ 188.43万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0600230%2F1
• 关键词: Genomic; analysis; malaria; resistance

Malaria is one of humankind‘s most persistent and deadly foes, and is a significant determinant of global poverty - causing debilitating illness in approximately half a billion people each year. The greatest burden of the disease falls on African children - over a million die each year of malaria.This project hinges on a key observation. Many people survive malaria infection and, after repeated exposure, develop some level of immunity.Our challenge is to answer this question. What are the natural immune responses that protect people from dying or becoming ill due to malaria? Here are two examples of what we mean by an immune response: (1) the person makes antibodies that attach to molecule X on the surface of the parasite; (2) when white blood cells come into contact with a malaria parasite they release chemical Y that kills the parasite. Knowing the answer to this question would help enormously in designing an effective malaria vaccine.Researchers have been tackling this question for almost a century - why is it so difficult to answer? Part of the problem is that people who are infected with malaria make a vast range of immune responses that have no protective benefit and some that may even be harmful. Searching through all these different immune responses to find those that protect people from becoming ill or dying is like searching for a needle in a haystack. To complicate matters further, much of the immune battle against the malaria parasite happens in the spleen and other inaccessible parts of the body that are very difficult to study in living people.Recent advances in human genome research are revolutionising the way that we tackle complex problems of this sort. The key observation is that most human genes show variation between individuals. By investigating how this natural genetic variation affects the ability of people to resist infection, we can get deep insights into molecular mechanisms of protective immunity.Why is this such a powerful approach? Firstly, because it doesn‘t require us to measure proteins directly, so we may be able to identify important mechanisms even if they are impossible to measure in living humans - e.g., if they are hidden away in the spleen. Secondly, because new technologies allow us to screen a vast number of genes without knowing anything about their function, making it possible to discover entirely novel mechanisms that are critical for protection against malaria.

疟疾是人类最持久和致命的敌人之一，是全球贫困的一个重要决定因素，每年约有5亿人因疟疾而患病。疟疾的最大负担福尔斯在非洲儿童身上--每年有100多万人死于疟疾。许多人在感染疟疾后存活下来，并在反复接触后产生一定程度的免疫力。我们的挑战是回答这个问题。什么是保护人们免于因疟疾而死亡或生病的自然免疫反应？这里有两个例子来说明我们所说的免疫反应：（1）人产生抗体，附着在寄生虫表面的分子X上;（2）当白色血细胞与疟疾寄生虫接触时，它们释放化学物质Y，杀死寄生虫。知道这个问题的答案对设计有效的疟疾疫苗将有很大的帮助。研究人员已经研究这个问题将近世纪了--为什么它这么难回答？部分问题在于，感染疟疾的人会产生广泛的免疫反应，这些免疫反应没有保护作用，有些甚至可能是有害的。在所有这些不同的免疫反应中寻找那些保护人们免于生病或死亡的免疫反应就像大海捞针一样。更复杂的是，免疫系统对抗疟原虫的大部分战斗发生在脾脏和人体其他难以触及的部位，这些部位在活人身上很难研究。人类基因组研究的最新进展正在彻底改变我们解决这类复杂问题的方式。关键的观察结果是，大多数人类基因在个体之间表现出变异。通过研究这种自然遗传变异如何影响人们抵抗感染的能力，我们可以深入了解保护性免疫的分子机制。为什么这是一种如此强大的方法？首先，因为它不需要我们直接测量蛋白质，所以我们可能能够识别重要的机制，即使它们不可能在活着的人类中测量-例如，如果它们藏在脾脏里的话第二，因为新技术使我们能够在不了解其功能的情况下筛选大量基因，从而有可能发现对预防疟疾至关重要的全新机制。