Signaling mechanisms linking infection, endocrine dysfunction, and growth failure

与感染、内分泌功能障碍和生长障碍相关的信号机制

• 批准号: 10318203
• 负责人: Michelle L Bland
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318203
• 关键词: Address; Animal Model; Animals; Binding; Campylobacter; Campylobacter infection; Campylobacter jejuni; ChIP-seq; Child; Childhood; Chronic; Chronic Childhood Arthritis; Complication; Crohn' s disease; Cytokine Signaling; Data; Diarrhea; Disease; Drosophila genus; Drosophila melanogaster; Endocrine; Endocrine disruption; Endotoxins; Escherichia coli; Event; Exhibits; Failure; Fat Body; Functional disorder; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Genomic approach; Genomics; Growth; Growth Hormone Signaling Pathway; Hepatocyte; Homologous Gene; Hormones; Immune; Immune response; Immune signaling; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune System; Insulin-Like Growth Factor I; Interleukin-1 beta; Laboratories; Larva; Lead; Learning Disabilities; Link; Liver; Mammals; Messenger RNA; Molecular; Mus; Mutation; NF-kappa B; Organ; Orthologous Gene; Pathway interactions; Patients; Pharmacology; Prevention; Principal Investigator; Production; Receptor Signaling; Regulation; Shigella; Signal Pathway; Signal Transduction; Site; Somatotropin; TLR4 gene; Tissues; Toll-like receptors; Transcript; Work; chronic infection; cognitive development; cognitive function; cognitive performance; cytokine; early childhood; enteric infection; enteric pathogen; fly; forward genetics; gastrointestinal; genetic approach; hormonal signals; hormone regulation; hormone resistance; in vivo; insulin-like peptide; loss of function mutation; novel therapeutics; pathogen; postnatal; promoter; rapid growth; receptor; recruit; response; stem; transcriptomics; whole genome

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.

儿童时期的感染和炎症性疾病会导致生长障碍。多种肠道病原体（例如弯曲杆菌属）的慢性同时感染。在世界许多地方，大肠杆菌是童年时期的常见现象。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慢。同样，患有炎症性疾病（例如幼年特发性关节炎或克罗恩病）的儿童比健康儿童要小。儿童期生长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 (Igf1) 基因功能丧失突变患者中常见的并发症。导致生长障碍的儿童感染和炎症性疾病与 IGF-1 低和生长激素 (GH) 水平升高有关，表明 GH 抵抗。然而，导致 GH 的信号事件 对感染和炎症反应的抵抗力尚不清楚。主要研究者的 实验室最近发现，遗传模型生物果蝇幼虫阶段先天免疫Toll信号通​​路的激活会导致生长障碍。活跃的 Toll 信号传导导致的生长减少源于果蝇胰岛素样肽 6 (Dilp6)（果蝇 IGF-1 的同源物）循环水平的有效降低。在此应用中，小鼠和果蝇的基因组和遗传学方法将用于研究先天免疫和炎症信号传导对动物生长的负调节。在目标 1 中，将研究 Dilp6 mRNA 水平降低的分子机制。主要研究人员的实验室将确定 NF-kB 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有助于整个动物生长和/或 Toll 信号下游 Dilp6 负调节的其他转录调节因子。在目标 2 中，感染期间 GH 抵抗的分子机制将是 调查了。主要研究人员的实验室将确定内毒素和促炎细胞因子信号转导与原代小鼠肝细胞中 GH 信号转导通路成分表达减少之间的转录机制，并将使用组织特异性遗传方法来确定肝脏中是否需要 MyD88（TLR4 和 IL-1ß 信号转导通路的常见成分）来抑制 GH 信号转导、IGF-1 的产生和生长。 对弯曲杆菌感染的反应。成功完成具体目标将确定感染和炎症广泛但人们知之甚少的后果背后的信号传导机制：内分泌功能障碍导致生长障碍。这里提出的工作将有助于我们了解先天免疫和炎症信号传导对激素调节和非免疫功能的控制。此外，这项工作可能会带来治疗慢性感染或炎症性疾病儿童生长障碍和预防认知障碍的新疗法。