NITRIC OXIDE AND SEVERE MALARIA

疟疾在全球范围内造成的死亡比任何其他寄生虫都多 疾病，然而对疾病病理生理学的充分理解是 对严重疟疾缺乏有效的治疗是有限的。 一氧化氮(NO)对多种细菌具有体外抗菌作用。 包括恶性疟原虫在内的各种微生物。最近， 我们注意到一氧化氮的产生和白细胞一氧化氮合酶2型的增加 (NOS2)在坦桑尼亚无症状疟疾儿童中的表达。 而NO的生成量和NOS2的表达则显著降低。 患有脑型疟疾的儿童。这项提案旨在延长 我们早期的工作是研究分子机制(S)负责的 病情严重时NO生成量和NOS2表达减少， 并确定这些发现是否出现在患有 不同的疟疾流行病学。我们将澄清NO和NOS2的作用 作为重症疟疾的分子标志物并检测其潜力 在重症发病机制中的作用。 我们的目标是：(I)确定全身性NO减少的机制 重度疟疾的产量和NOS2的表达；(2)确定是否 有某些nos2和细胞因子基因的等位基因标记与 以及(3)确定NO是否也是相反的 其他年龄组疟疾严重程度的分子相关性(成人与 儿童)和疟疾流行情况不同的地区(印度尼西亚 VS坦桑尼亚)。 实现这些目标将极大地增进我们对 严重疟疾的发病机制。此外，这项工作可能会 为重症肺炎的治疗和预防带来新的战略 疟疾。

Malaria causes more mortality globally than any other parasitic disease, yet a full understanding of disease pathophysiology is lacking, and effective treatments for severe malaria are limited. Nitric oxide (NO) has antimicrobial effects in vitro against a wide variety of microorganisms including Plasmodium falciparum. Recently, we noted increased NO production and leukocyte NO synthase type 2 (NOS2) expression in Tanzanian children with asymptomatic malaria. However, NO production and NOS2 expression were markedly decreased in children with cerebral malaria. This proposal is designed to extend our earlier work to examine the molecular mechanism(s) responsible for the decreases in NO production and NOS2 expression in severe disease, and to determine if these findings are seen in adults in a region with different malaria epidemiology. We will clarify the role of NO and NOS2 as molecular markers in severe malaria and examine their potential roles in the pathogenesis of severe disease. Our aims are to (i) determine the mechanism for decreased systemic NO production and NOS2 expression in severe malaria; (2) determine if there are certain NOS2 and cytokine gene allelic markers associated with severe malaria, and (3) establish whether NO is also an inverse molecular correlate of malaria severity in other age groups (adults vs children) and in regions with different malaria epidemiology (Indonesia vs Tanzania). Accomplishing these goals will add greatly to our overall understanding of the pathogenesis of severe malaria. Furthermore, this work may result in novel strategies for the treatment and prevention of severe malaria.