GENETIC BASIS OF SEVERE MALARIAL ANEMIA

严重疟疾贫血的遗传基础

• 批准号: 6763103
• 负责人: Douglas Jay Perkins
• 金额: $ 57.81万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763103
• 关键词: Africa; Plasmodium falciparum; anemia; clinical research; cytokine; gene expression; genetic polymorphism; genetic susceptibility; human subject; immunoregulation; infant human (0-1 year); interleukin 10; interleukin 12; longitudinal human study; malaria; medical complication; migration inhibition factor; nitric oxide; pathologic process; patient oriented research; preschool child (1-5); prostaglandin E; transforming growth factors; tumor necrosis factor alpha

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.

描述（由申请人提供）：居住在疟疾传播大流行地区（例如肯尼亚西部）的儿童因严重疟疾贫血（SMA）而出现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，与 SMA 相关的发病率和死亡率最高发生在出生至 2 岁之间的儿童中。因此，我们将调查居住在肯尼亚基苏木的幼儿中 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，因此我们将重点定义细胞因子的作用[白细胞介素（IL）-12、肿瘤坏死因子（TNF）-α、巨噬细胞迁移抑制因子（MIF）、IL-10和转化生长因子 (TGF)-β1]，以及效应分子 [一氧化氮 (NO) 和 前列腺素 (PG)-E2] 在 SMA 免疫发病机制中的作用。该提案的目标是：1) 确定与 SMA 的发展和结果相关的细胞因子和效应分子基因表达的独特特征，2) 确定细胞因子和效应分子基因的多态性是否导致细胞因子平衡不平衡，影响 SMA 的临床病程和结果，3) 识别与 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了促进疟疾贫血的复杂遗传、炎症和临床因素，将提供重要的信息。 有关疟疾候选疫苗未来开发和测试的信息。