THE ROLE OF INSULIN IN HUMAN FETAL LUNG DEVELOPMENT

胰岛素在人类胎儿肺发育中的作用

• 批准号: 6702582
• 负责人: Jeanne Marie Snyder
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702582
• 关键词: biological signal transduction; cell line; clinical research; developmental genetics; diabetes mellitus; embryo /fetus protein; gene expression; genetic regulatory element; histogenesis; hormone regulation /control mechanism; human fetus tissue; immunocytochemistry; insulin; insulin receptor; lung; lung development; phosphatidylinositol 3 kinase; phosphorylation; protein kinase; protein localization; protein protein interaction; proteolipids; pulmonary surfactants; respiratory distress syndrome of newborn; respiratory epithelium; transcription factor

DESCRIPTION: (Adapted from the Investigator's Abstract): The hypothesis is that delayed lung development in the fetus of the diabetic woman is related to surfactant-associated protein deficiency caused by high levels of insulin. Aim 1 is to elucidate the signal transduction pathways involved in insulin-mediated inhibition of SP-A and SP-B gene expression. Signal transduction inhibitors, enzyme assays, characterization of signaling intermediates and transfection with dominant negative and constitutively active constructs will be used to test the hypothesis that the PI-3K signal transduction pathway mediates the effects of insulin. Aim 2 is to identify the cis-acting elements in the SP-A and SP-B genes which mediate the inhibitory effects of insulin. Luciferase reporter gene constructs will be used to localize inhibitory insulin response elements in the 5' flanking region of the human SP-A1 and SP-A2 genes. Aim 3 is to identify the transcription factors that interact with the SP-A1 and SP-B insulin response elements. Electrophoretic mobility shift assays will be used to test the hypothesis that HNF-3a and C/EBPa mediate the insulin-induced inhibition of SP-A and SP-B gene expression. Aim 4 is to describe the molecular events (phosphorylation, localization, and/or changes in gene expression) that link signal transduction to transcription factors which interact with the insulin response elements in the SP-A1 and SP-B genes.

描述：(改编自《调查者摘要》)：假设是 糖尿病妇女胎儿肺发育迟缓与 高胰岛素引起的表面活性物质相关蛋白缺乏症。目标 1阐明了胰岛素介导的信号转导途径 抑制SP-A、SP-B基因表达。信号转导抑制剂， 酶分析、信号中间产物的特性和转染法 具有主要的否定和构造活性的构造将被用于 验证PI-3K信号转导通路介导 胰岛素的作用。目标2是确定SP-A中的顺式作用元件 以及介导胰岛素抑制作用的SP-B基因。荧光素酶 报告基因构建将用于定位抑制的胰岛素反应 人SP-A1和SP-A2基因5‘侧翼区的元件。目标3是 鉴定与SP-A1和SP-B相互作用的转录因子 胰岛素反应元件。将使用电泳迁移率变化分析 验证HNF-3a和C/EBPA介导胰岛素诱导的假说 抑制SP-A、SP-B基因表达。目标4是描述分子 事件(磷酸化、定位和/或基因表达的变化) 将信号转导与转录因子联系起来，转录因子与 SP-A1和SP-B基因中的胰岛素反应元件。

项目成果

Insulin utilizes the PI 3-kinase pathway to inhibit SP-A gene expression in lung epithelial cells.

• DOI: 10.1186/rr191
• 发表时间: 2002
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Miakotina OL;Goss KL;Snyder JM
• 通讯作者: Snyder JM

Surfactant protein A in rabbit sinus and middle ear mucosa.

兔鼻窦和中耳粘膜中的表面活性蛋白A。

• DOI: 10.1177/000348949910801001
• 发表时间: 1999
• 期刊: The Annals of otology, rhinology, and laryngology
• 作者: Dutton,JM;Goss,K;Khubchandani,KR;Shah,CD;Smith,RJ;Snyder,JM
• 通讯作者: Snyder,JM

Antisense inhibition of epidermal growth factor receptor decreases expression of human surfactant protein A.

表皮生长因子受体的反义抑制可降低人表面活性剂蛋白 A 的表达。

• DOI: 10.1165/ajrcmb.22.6.3726
• 发表时间: 2000
• 期刊: American journal of respiratory cell and molecular biology.
• 作者: Klein,JM;McCarthy,TA;Dagle,JM;Snyder,JM
• 通讯作者: Snyder,JM

Signal transduction events involved in TPA downregulation of SP-A gene expression.

信号转导事件涉及 TPA 下调 SP-A 基因表达。

• DOI: 10.1152/ajplung.00416.2003
• 发表时间: 2004
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Miakotina,OlgaL;Snyder,JeanneM
• 通讯作者: Snyder,JeanneM

O2 regulates surfactant protein A mRNA transcription and stability in human fetal lung in vitro.

O2 在体外调节人胎肺中表面活性蛋白 A mRNA 的转录和稳定性。

• DOI: 10.1152/ajplung.1998.274.3.l343
• 发表时间: 1998
• 期刊: The American journal of physiology
• 作者: Acarregui,MJ;Kumar,AR;Penisten,ST;Snyder,JM
• 通讯作者: Snyder,JM