Signaling mechanisms linking infection, endocrine dysfunction, and growth failure

儿童时期的感染和炎性疾病会导致生长障碍。慢性和同时感染多种肠道病原体，如弯曲杆菌属。大肠杆菌是世界上许多地方儿童的常见疾病。患有这些感染的儿童，即使他们没有腹泻症状，也会表现出线性生长下降。同样，患有炎性疾病的儿童，如幼年特发性关节炎或克罗恩病，比健康儿童要小。儿童期生长发育迟缓与认知功能受损有关，这是慢性肠道病原体感染儿童和胰岛素样生长因子-1（Igf 1）基因功能缺失突变患者中常见的并发症。导致生长失败的儿童感染和炎性疾病与低IGF-1和高生长激素（GH）水平相关，表明GH抵抗。然而，导致GH的信号事件 对感染和炎症的抗性还不清楚。主要研究者 实验室最近发现，在遗传模式生物黑腹果蝇（Drosophila melanogaster）的幼虫阶段，先天免疫Toll信号传导途径的激活导致生长失败。由Toll信号传导引起的生长减少源于果蝇胰岛素样肽6（Dilp 6）循环水平的有效降低，Dilp 6是IGF-1的苍蝇同系物。在本申请中，小鼠和果蝇的基因组和遗传方法将用于研究先天免疫和炎症信号对动物生长的负调节。在目标1中，将研究Dilp 6 mRNA水平降低的分子机制。主要研究者的实验室将确定Dif（NF-kB的同源物）是否直接与Dilp 6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有助于整个动物生长和/或Toll信号下游Dilp 6的负调控的其他转录调节因子。在目标2中，感染过程中GH耐药的分子机制将是 研究了主要研究者的实验室将确定将内毒素和促炎细胞因子信号传导与原代小鼠肝细胞中GH信号传导途径组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MyD 88（TLR 4和IL-1 β信号传导途径的共同组分）是否需要在肝脏中抑制GH信号传导，IGF-1的产生和生长响应弯曲杆菌感染。成功完成特定目标将确定感染和炎症的广泛但知之甚少的后果的信号传导机制：导致生长失败的内分泌功能障碍。本文提出的工作将有助于我们理解激素调节和先天免疫和炎症信号对非免疫功能的控制。此外，这项工作可能会导致新的疗法，用于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。

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.