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生长衰竭。在世界许多地方，慢性和同时感染多种肠病原体，如弯曲杆菌和大肠杆菌，是儿童的一个常见方面。患有这些感染的儿童，即使没有腹泻症状，也会表现出线性生长减少。同样，患有炎症性疾病的儿童，如青少年特发性关节炎或克罗恩病，比健康儿童要小。儿童生长减缓与认知功能受损有关，认知功能受损是慢性肠病原体感染儿童和胰岛素样生长因子-1 （Igf1）基因功能缺失突变患者的并发症。导致生长衰竭的儿童感染和炎症性疾病与低IGF-1和生长激素（GH）水平升高有关，表明生长激素耐药性。然而，导致生长激素的信号事件

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.