Signaling mechanisms linking infection, endocrine dysfunction, and growth failure

儿童时期的感染和炎症性疾病会导致发育障碍。慢性同时感染多种肠道病原体，如弯曲杆菌。在世界上许多地方，大肠杆菌是童年的常态。患有这些感染的儿童，即使在没有腹泻症状的情况下，也会表现出线性生长减慢。同样，患有炎症性疾病的儿童，如幼年特发性关节炎或克罗恩病，比健康儿童更小。儿童发育减慢与认知功能受损有关，这是一种并发症，见于患有慢性肠道病原体感染的儿童和胰岛素样生长因子-1(IGF1)基因功能丧失突变的患者。导致生长障碍的儿童感染和炎症性疾病与IGF-1水平低和生长激素(GH)水平升高有关，这表明GH抵抗。然而，导致GH的信号事件 对感染和炎症的抗药性尚不清楚。首席调查员的 实验室最近发现，遗传模式生物黑腹果蝇幼虫阶段先天免疫Toll信号通路的激活会导致生长失败。活跃的Toll信号导致的生长减少源于果蝇胰岛素样肽6(Dilp6)循环水平的有效降低，Dilp6是IGF-1的苍蝇同源物。在这项应用中，将使用小鼠和果蝇的基因组和遗传学方法来研究先天免疫和炎症信号对动物生长的负面调节。在目标1中，将研究Dilp6mRNA水平降低的分子机制。首席研究人员的实验室将确定核因子-kB的同源物Dif是否直接与Dilp6启动子结合以抑制其表达，并将使用正向遗传学方法来寻找额外的转录调节因子，这些转录调节因子有助于对整个动物的生长和/或Toll信号下游的Dilp6进行负调控。在目标2中，感染期间产生生长激素抵抗的分子机制将是 调查过了。主要研究人员的实验室将确定将内毒素和促炎细胞因子信号与原代小鼠肝细胞GH信号通路成分表达减少联系起来的转录机制，并将使用组织特异性遗传方法来确定肝脏是否需要TLR4和IL-1？信号通路的共同成分MyD88来抑制GH信号、IGF-1的产生和生长，以应对弯曲杆菌感染。成功完成特定的目标将确定感染和炎症广泛但鲜为人知的后果背后的信号机制：内分泌功能障碍导致生长障碍。本文提出的工作将有助于我们理解激素调节和通过先天免疫和炎症信号控制非免疫功能。此外，这项工作可能会导致治疗患有慢性感染或炎症性疾病的儿童的生长障碍和预防认知障碍的新疗法。

Infections and inflammatory diseases during childhood cause growth failure. Chronic and simultaneous infection with multiple enteropathogens such as Campylobacter spp. and Escherichia coli is a regular aspect of childhood in many parts of the world. Children suffering from these infections, even when they are asymptomatic for diarrhea, exhibit reduced linear growth. Similarly, children with inflammatory diseases such as juvenile idiopathic arthritis or Crohn's disease are smaller than healthy children. Reduced childhood growth is linked to impaired cognitive function, a complication seen in children with chronic enteropathogen infections and in patients with loss-of-function mutations in the insulin-like growth factor-1 (Igf1) gene. Childhood infections and inflammatory diseases that lead to growth failure are associated with low IGF-1 and elevated growth hormone (GH) levels, indicating GH resistance. However, the signaling events that lead to GH resistance in response to infection and inflammation are not understood. The principal investigator's laboratory recently made the discovery that activation of the innate immune Toll signaling pathway in the larval stage of the genetic model organism Drosophila melanogaster leads to growth failure. Reduced growth caused by active Toll signaling stems from a potent reduction in circulating levels of Drosophila insulin-like peptide 6 (Dilp6), the fly homolog of IGF-1. In this application, genomic and genetic approaches in the mouse and the fruit fly will be used to investigate the negative regulation of animal growth by innate immune and inflammatory signaling. In Aim 1, the molecular mechanisms underlying reduced Dilp6 mRNA levels will be investigated. The principal investigator's lab will determine whether Dif, a homolog of NF-kB, binds directly to the Dilp6 promoter to inhibit its expression and will use a forward genetics approach to find additional transcriptional regulators that contribute to the negative regulation of whole-animal growth and/or Dilp6 downstream of Toll signaling. In Aim 2, molecular mechanisms underlying GH resistance during infection will be investigated. The principal investigator's lab will identify transcriptional mechanisms linking endotoxin and pro-inflammatory cytokine signaling to reduced expression of components of the GH signaling pathway in primary mouse hepatocytes and will use a tissue-specific genetic approach to determine whether MyD88, a common component of the TLR4 and IL-1ß signaling pathways is required in liver to inhibit GH signaling, IGF-1 production and growth in response to Campylobacter infection. Successful completion of the Specific Aims will identify signaling mechanisms underlying a widespread but poorly understood consequence of infection and inflammation: endocrine dysfunction leading to growth failure. The work proposed here will contribute to our understanding of hormone regulation and the control of non-immune functions by innate immune and inflammatory signaling. Furthermore, this work may lead to new therapies for treatment of growth failure and prevention of cognitive impairment in children suffering from chronic infections or inflammatory diseases.