APOLIPOPROTEIN E ALLELES IN MODULATING TRYPANOSOMA

在动脉粥样硬化和阿尔茨海默病等老年疾病的遗传流行病学中，一个尚未解决的主要问题是，为什么有害的载脂蛋白E epsilon 4等位基因出现在我们的祖先中。我们的论文(马丁，衰老的神经生物学2：441-443,1999)认为，该等位基因是为了抵抗脂类病原体的感染而选择的。在这项提案中，我们测试了一种特定的候选生物体--布鲁氏锥虫，这是一种原生动物，是非洲许多地区地方性感染的原因，当感染涉及大脑时，它与高死亡率有关(非洲昏睡病)。作为对这一假设的初步探讨，我们建议跟踪布鲁氏毛滴虫在实验感染的转基因C57BL/6小鼠的血流中的复制动力学，这些转基因小鼠被设计为在其内源APOE基因座的位置表达人APOE epsilon 3或epsilon 4等位基因(“敲门”小鼠)。我们预测对布鲁氏毛滴虫攻击的易感性将增加，从对epsilon 4纯合子相对耐药的小鼠品系，到杂合子(epsilon3/epsilon4)，再到高度易感的epsilon3纯合子。如果这一假设得到支持，未来的方向可能包括将实验扩展到其他APOE等位基因(例如，APOE epsilon 4，以及我们的团队在另一项研究中定义的各种人类单倍型)，对感染抗性机制的研究，以及在人类群体中进行流行病学研究，在这些研究中，可以测试各种APOE单倍型在赋予布鲁氏菌耐药性方面的作用。

A major unsolved question in the genetic epidemiology of late life diseases such as atherosclerosis and Alzheimer disease is why the deleterious APOE epsilon4 allele emerged in our progenitors. Our thesis (Martin, Neurobiology of Aging 2:441-443, 1999) is that this allele was selected for resistance to infection by lipophylic pathogens. In this proposal, we test a specific candidate organism, Trypanosoma brucei brucei, a protozoan that is the cause of endemic infections in many regions of Africa and is associated with a high mortality rate when infections involve the brain (African sleeping sickness). As an initial approach to this hypothesis, we propose to follow the kinetics of replication of T. brucei in the blood stream of experimentally infected transgenic C57Bl/6 mice that have been engineered to express either the human APOE epsilon3 or epsilon4 alleles at the sites of their endogenous APOE loci ("knockin" mice). We predict an increasing gradient of susceptibility to challenge w ith T. brucei, from the relatively resistant strains of mice homozygous for epsilon4, to heterozygotes (epsilon3/epsilon4), to highly susceptible epsilon3 homozygotes. If the hypothesis is supported, future directions could include extensions of the experiments to other APOE alleles (e.g., APOE epsilon 4 and, as they are being defined by our group in another study, various human haplotypes), studies of the mechanisms of resistance to infection, and epidemiological studies in human populations, in which the role of various APOE haplotypes in conferring resistance to T. brucei can be tested.