Gestational Programming of Nephrogenesis

肾发生的妊娠规划

• 批准号: 8056791
• 负责人: Thomas R Magee
• 金额: $ 7.38万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056791
• 关键词: Abbreviations; Adult; Anatomy; Angiotensin Receptor; Animal Model; Apoptosis; Binding; Blood Pressure; Cardiovascular Diseases; Cell surface; Chromatin; Data; Development; Down-Regulation; Embryo; Environment; Epidemiologic Studies; Epigenetic Process; Event; 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; Mediating; Mesenchyme; Metabolic syndrome; Metanephric Diverticulum; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Mutation; Nephroblastoma; Nephrons; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Notch Signaling Pathway; Nutrient; Obesity; Organ; Pathway interactions; Pattern; 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）：母亲营养不良（MUN）导致胎儿宫内生长受限（IUGR），这显著增加了成年后患心脏病、肥胖、II型糖尿病和其他代谢综合征的风险。iugr相关的肾脏编程导致成人肾减少（肾小球数量减少）和成人动脉血压升高。预防这种形式的程序性肾损伤的机制和策略尚不清楚。研究人员最近发现，在MUN肾形成过程中，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输尿管反复芽分支、MAPK/ERK信号和肾素-血管紧张素系统基因表达减少，最终导致肾小球数量减少、肾小球成熟异常和成人高血压。在这一过程中的一个早期事件，WT1上调，是由表观遗传MUN编程调节的。在研究者的模型中，母鼠从妊娠第10天到出生后第8天喂食减少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形成易受IUGR影响的关键时间点。他们将通过实时RT-PCR和Western blotting检测GDNF和Notch信号通路、MAPK/ERK激活和肾内RAS基因表达的程序性下调，并通过免疫组织化学和原位杂交检测肾和肾小球区域表达。WT1的表观遗传规划将被表征。为了证实可能的信号传导机制，研究人员将利用重组蛋白、siRNA和病毒基因表达载体在体外MFR肾外植体中诱导GDNF和Notch信号通路的过表达，以复制/阻止IUGR对输尿管分支、肾小球形成和信号转导通路的影响。这些发现将提供MUN对程序性肾形成影响的机制分析，并为治疗人类胎儿程序性肾形成提供一个翻译框架。