GENETIC BASIS OF SEVERE MALARIAL ANEMIA

描述（由申请人提供）：居住在疟疾传播的全流行地区（如肯尼亚西部）的儿童因严重疟疾贫血（SMA）而发生危及生命的并发症的风险增加。我们最近在这一领域的研究结果表明，SMA相关的发病率和死亡率最高的发生在出生至2岁的儿童中。因此，我们将调查居住在肯尼亚基苏穆的儿童SMA的遗传和免疫机制。由于控制疟疾感染需要有效的细胞介导的免疫，因此我们将集中于确定细胞因子[白细胞介素（IL）-12、肿瘤坏死因子（TNF）-α、巨噬细胞移动抑制因子（MIF）、IL-10和转化生长因子（TGF）-β 1]和效应分子[一氧化氮（NO）和 前列腺素（PG）-E2]在SMA免疫发病机制中的作用。本提案的目的是：1）确定与SMA的发展和结局相关的细胞因子和效应分子基因表达的独特谱，2）确定细胞因子和效应分子基因的多态性是否导致影响SMA临床病程和结局的细胞因子平衡失衡，3）确定与SMA免疫发病机制相关的新基因表达模式。该提案的总体目标是确定免疫调节基因，其关键表达模式是SMA疾病易感性的基础。该项目的成功完成，考虑到复杂的遗传，炎症和临床因素，促进疟疾贫血，将提供重要的 为今后开发和测试疟疾候选疫苗提供信息。

DESCRIPTION (provided by applicant): Children residing in holoendemic regions of malaria transmission, such as western Kenya, are at an increased risk for developing life-threatening complications due to severe malarial anemia (SMA). Our recent findings in this area illustrate that the highest rates of SMA-associated morbidity and mortality occur in children between birth and 2 years of age. Therefore, we will investigate the genetic and immunologic mechanisms of SMA in young children residing in Kisumu, Kenya. Since effective cell-mediated immunity is required for controlling malaria infection, we will focus on defining the role of cytokines [interleukin (IL )-12, tumor necrosis factor (TNF)-alpha, macrophage migration inhibitory factor (MIF), IL-10 and transforming growth factor (TGF)-beta1], and effector molecules [nitric oxide (NO) and prostaglandin (PG)-E2] in the immunopathogenesis of SMA. The goals of this proposal are: 1) to identify unique profiles of cytokine and effector molecule gene expression associated with the development and outcome of SMA, 2) to determine if polymorphisms in the cytokine and effector molecule genes lead to disequilibrium in the cytokine balance that affects the clinical course and outcome of SMA, and 3) to identify novel patterns of gene expression associated with the immunopathogenesis of SMA. The overall goal of this proposal is to identify the immunomodulatory genes, whose critical patterns of expression underlie disease susceptibility to SMA. Successful completion of this project, that takes into account the complex genetic, inflammatory, and clinical factors that promote malarial anemia, will offer important information for the future development and testing of malaria vaccine candidates.