Inflammation, Iron, and Cognition in S. japonicum

描述（由申请人提供）：本提案的总体目标是前瞻性研究日本血吸虫病相关认知障碍的机制。我们将使用日本血吸虫感染状态的变化作为模型来理解在一系列寄生虫感染中观察到的认知障碍机制。本提案中提出的假设对促进旺盛的促炎细胞因子反应的许多儿童疾病具有更广泛的意义。我们建议探索日本血吸虫与认知功能下降之间已知因果关系的生物学机制。在18个月的随访期间，我们将利用日本血吸虫再次感染时发生的促炎细胞因子（tnf - α和IL-6）水平的变化来研究它们作为认知障碍介质的作用。更全面地了解寄生虫感染和发病率之间关系的机制是我们对儿童疾病干预措施概念化的基础。本研究的目的是：1)前瞻性地确定日本血吸虫反应产生的促炎细胞因子与认知功能的关系。采用纵向设计，我们将建立促炎细胞因子与认知功能之间的关系，因为受试者从治疗后未感染状态（化疗治愈后6周）转移到在18个月随访期间的五个时间点再次感染状态。我们假设认知功能测试的表现与日本血吸虫再感染后产生的促炎细胞因子水平呈负相关，并由这些细胞因子对中枢神经系统的直接毒性作用介导。2)前瞻性研究寄生虫病背景下宿主铁状态与认知功能的关系。我们将研究炎症性贫血在宿主对寄生虫病的促炎免疫反应相关的认知障碍中的作用。具体来说，我们将研究通过血清转铁蛋白受体水平测量的生物可利用铁减少在寄生虫病相关认知障碍发病机制中的作用。我们假设宿主对寄生虫病的促炎免疫反应通过炎症性贫血降低铁的生物利用度，这反过来又对认知功能产生负面影响。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to prospectively investigate the mechanisms of Schistosomiasis japonicum associated cognitive impairment. We will use changes in S. japonicum infection status as a model for understanding mechanisms of cognitive impairment observed in a range of parasitic infections. The hypotheses addressed in this proposal have broader implications for a host of diseases of childhood that promote an exuberant pro-inflammatory cytokine response. We propose to explore the biologic mechanisms underlying the known causal relationship between S. japonicum and decreased cognitive function. We will utilize the changes in levels of pro-inflammatory cytokines (TNF-alpha and IL-6) which occur with S. japonicum re-infection during an 18 month period of follow-up to investigate their role as mediators of cognitive impairment. A fuller understanding of the mechanisms underlying the relationship between parasitic infections and morbidity is fundamental to our conceptualization of interventions for childhood diseases. The aims of this study are: 1) to prospectively determine the relationship between pro-inflammatory cytokines made in response to S. japonicum and cognitive function. Using a longitudinal design, we will establish the relationship between proinflammatory cytokines and cognitive function as subjects move from a post-treatment, uninfected state (six weeks after chemotherapeutic cure) to an increasingly re-infected state at five time points over an 18 month period of follow-up. We hypothesize that performance on tests of cognitive function will be inversely related to levels of pro-inflammatory cytokines made in response to S. japonicum re-infection and be mediated by the direct toxic effects of these cytokines on the central nervous system. 2) To prospectively determine the relationship between host iron status and cognitive function in the context of parasitic diseases. We will investigate the role of anemia of inflammation in cognitive impairment related to host pro-inflammatory immune response to parasitic diseases. Specifically, we will investigate the role of decreased bio-available iron as measured by serum transferrin receptor levels in the pathogenesis of parasitic disease related cognitive impairment. We hypothesize that host's pro-inflammatory immune responses to parasitic diseases decrease the bioavailability of iron through anemia of inflammation, which, in turn, negatively impacts cognitive function.