Gestational Programming of Nephrogenesis

肾发生的妊娠规划

• 批准号: 7790498
• 负责人: Thomas R Magee
• 金额: $ 7.69万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790498
• 关键词: Abbreviations; Adult; Anatomy; Angiotensin Receptor; Animal Model; Apoptosis; Binding; Blood Pressure; Brain; Cardiovascular Diseases; Cell surface; Chromatin; Data; Development; Down-Regulation; Embryo; Environment; Epidemiologic Studies; Epigenetic Process; Event; Extracellular Signal Regulated Kinases; Fetal Growth Retardation; Fetal Kidney; Fetus; Gene Expression; Genetic Transcription; Glucocorticoids; Goals; Growth; Growth Factor; HRAS gene; Histones; Homeobox; Human; Hypertension; Immunohistochemistry; Immunoprecipitation; In Situ Hybridization; Injury; Investigation; Ion Transport; Kidney; Kidney Failure; Low Birth Weight Infant; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Mediating; Mesenchyme; Metabolic syndrome; Metanephric Diverticulum; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Morphogenesis; Mutation; Nephroblastoma; Nephrons; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Notch Signaling Pathway; Nutrient; Obesity; Organ; Pathway interactions; Pattern Formation; Perinatal; Phenotype; Phosphotransferases; Physical condensation; Placental Insufficiency; Pregnancy; Prevention strategy; Process; Proteins; Rattus; Recombinant Proteins; Reducing diet; Renin-Angiotensin System; Research Design; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Staging; Stream; Therapeutic; Time; Type 2 Angiotensin II Receptor; Up-Regulation; Viral Genes; WNT11 gene; WNT4 gene; WT1 gene; Weight Gain; Western Blotting; base; expression vector; feeding; fetal; fetal programming; heart disease risk; insight; mother nutrition; nephrogenesis; neurotrophic factor; notch protein; nutrition; offspring; postnatal; prevent; programs; proto-oncogene protein c-ret; receptor; transcription factor

DESCRIPTION (Provided by Applicant): Maternal under-nutrition (MUN) results in intrauterine growth restriction (IUGR) of the fetus, which markedly increases the lifelong adult risk of heart disease, obesity, type II diabetes, and other components of the metabolic syndrome. IUGR-related programming of the kidney gives rise to adult nephropenia (reduced glomerular number) and elevation in adult arterial blood pressure. Mechanisms for and strategies for prevention of this form of programmed renal injury are poorly understood. The investigators recently identified significant down-regulation of the Glial derived neurotrophic factor (GDNF) and Notch signaling pathways during MUN nephrogenesis. They hypothesize that programmed down-regulation of these signaling pathways leads to a reduction of iterative ureteric bud branching, MAPK/ERK signaling, and renin-angiotensin system gene expression, which ultimately results in reduced glomerular number, abnormal glomerular maturation, and adult hypertension. A proposed early event in this process, WT1 upregulation, is modulated by epigenetic MUN programming. In the investigators' model, maternal rat dams are fed a 50% reduced diet from day 10 of gestation to postnatal day 8. They will identify the key time point during fetal kidney development when ureteric branching and glomerulogenesis are susceptible to IUGR. They will examine the programmed down-regulation of the GDNF and Notch signaling pathways, MAPK/ERK activation, and intra-renal RAS gene expression by real time RT-PCR and Western blotting, as well as regional kidney and glomerular expression by immunohistochemistry and in situ hybridization. Epigenetic programming of WT1 will be characterized. To confirm the putative signaling mechanisms, the will induce over-expression of the GDNF and Notch signaling pathways using recombinant protein, siRNA, and viral gene expression vectors in ex vivo MFR kidney explants to replicate/prevent the effects of IUGR on ureteric branching, glomerular formation, and signal transduction pathways. These findings will provide a mechanistic analysis of the impact of MUN on programmed nephrogenesis, and provide a translational framework for treating fetal programming in humans. RELEVANCE: Low birth weight newborns are born with kidneys deficient in nephron number as well as permanent changes in gene expression due to the maladaptive fetal environment. These studies are designed to provide insights into the molecular changes in kidney development that occur due to this form of fetal programming. The investigators' long term goal is to identify key developmental points in fetal kidney growth and to reverse the condition through therapeutic treatments

描述（由申请人提供）：母体营养不良（MUN）导致胎儿宫内生长受限（IUGR），这显著增加了心脏病、肥胖、II型糖尿病和代谢综合征其他组分的终身成人风险。 IUGR相关的肾脏编程引起成人肾病（肾小球数量减少）和成人动脉血压升高。 机制和策略，预防这种形式的程序性肾损伤知之甚少。 研究人员最近发现，在MUN肾发生过程中，胶质源性神经营养因子（GDNF）和Notch信号通路显著下调。 他们假设这些信号通路的程序性下调导致迭代输尿管芽分支、MAPK/ERK信号传导和肾素-血管紧张素系统基因表达的减少，最终导致肾小球数量减少、肾小球成熟异常和成人高血压。 在这个过程中提出的早期事件，WT 1上调，是由表观遗传MUN编程调制。 在研究者的模型中，从妊娠第10天到出生后第8天，母鼠饲喂减少50%的饮食。 他们将确定胎儿肾脏发育过程中输尿管分支和肾小球发生易受IUGR影响的关键时间点。 他们将通过真实的时间RT-PCR和蛋白质印迹检测GDNF和Notch信号通路的程序性下调、MAPK/ERK激活和肾内RAS基因表达，以及通过免疫组织化学和原位杂交检测局部肾脏和肾小球表达。 WT 1的表观遗传编程将被表征。 为了证实推定的信号传导机制，将在离体MFR肾外植体中使用重组蛋白、siRNA和病毒基因表达载体诱导GDNF和Notch信号传导途径的过度表达，以复制/预防IUGR对输尿管分支、肾小球形成和信号传导途径的影响。这些发现将为MUN对程序性肾发生的影响提供机制分析，并为治疗人类胎儿编程提供翻译框架。 相关性：低出生体重新生儿出生时肾单位数量不足，以及由于胎儿环境适应不良导致的基因表达永久性变化。 这些研究旨在深入了解由于这种形式的胎儿编程而发生的肾脏发育中的分子变化。 研究人员的长期目标是确定胎儿肾脏生长的关键发育点，并通过治疗性治疗逆转病情。