Feto-maternal DNA/RNA Trafficking: Biology and Application

胎儿-母体 DNA/RNA 贩运：生物学和应用

基本信息

批准号：
8054127
负责人：
DIANA W. BIANCHI
金额：
$ 0.8万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8054127
关键词：
Achievement Affect Amniotic Fluid Anatomy Aneuploidy Biological Biological Assay Biological Markers Biological Process Biology Blood Body Fluids Cells Cerebrospinal Fluid Chromosome abnormality Chromosomes Clinical Complex Computer software Congenital adrenal hyperplasia Correlation Studies Custom DNA Data Data Set Deformity Detection Development Developmental Gene Diagnostic Diagnostic tests Dimensions Disease Down Syndrome Evaluation Fetal Development Fetal Diseases Fetal Therapies Fetus Functional disorder Gastroschisis Gender Gene Expression Genes Genitalia Genomics Gestational Age Goals Growth Hypoxia Image Inflammation Lead Link Macaca mulatta Measurement Messenger RNA Meta-Analysis Nucleic Acids Pathway interactions Plasma Pregnancy Pregnancy Complications Prenatal Diagnosis Procedures Protein Analysis Role Sampling Screening procedure Second Pregnancy Trimester Serum Serum Proteins Testing Tissues Ultrasonography Urine Whole Blood Woman Work bench to bedside clinical application clinically significant fetal fetus at risk insight malformation noninvasive diagnosis novel novel diagnostics novel strategies post intervention prenatal prenatal therapy research study trafficking

项目摘要

Project Summary Current means of prenatal diagnosis and screening involve three different types of assays: measurements of serum proteins, fetal imaging through sonography, and chromosome analysis. In this application we propose to add a new dimension to fetal evaluation by developing an understanding of cell-free nucleic acids as novel biomarkers of normal and abnormal fetal functional development at different gestational ages. Over the past four years this field has expanded exponentially, encompassing evaluation of fetal and placental DNA and mRNA in maternal blood, amniotic fluid, cerebrospinal fluid, and urine. Recently, noninvasive diagnosis of fetal Rhesus D status, using cell-free fetal DNA in maternal blood, has made the transition from bench to bedside. We now propose new studies that will build upon the achievements in project years 1-4. In aim 1 we will test the hypothesis that cell-free DNA (total and fetal) has biological significance and clinical applications during pregnancy. We will examine the clinical utility of fetal gender detection in X-linked conditions, in fetuses at risk for congenital adrenal hyperplasia, and in fetuses with ambiguous genitalia. We will also examine the significance of levels of total cell-free DNA as a noninvasive marker of tissue hypoxia and inflammation. In aim 2 we will test the hypothesis that normal and abnormal fetal gene expression can be distinguished from each other using cell-free mRNA in maternal body fluids such as whole blood and amniotic fluid. Our goal is to develop a panel of key genes that distinguish between normal and abnormal fetuses, which will permit development of custom microarrays for specific prenatal diagnostic applications. In aim 3 we will determine whether one can use genomic approaches to better understand fetal development. Using existing software packages we will analyze the lists of differentially-regulated genes acquired in aim 2 to examine where and when specific fetal genes are expressed. We will identify key biological pathways that are involved in normal and abnormal fetal development, and are affected by fetal treatment procedures. We will also use new genomic approaches, such as network analyses, to understand complex biological relationships. Successful completion of the proposed experimental plan will significantly expand the current scope of prenatal diagnosis beyond anatomy, aneuploidy, and single gene disorder detection. Genomic analysis will lead to new insights into the pathophysiology of fetal chromosomal and anatomic abnormalities, which will ultimately lead to rational and entirely novel approaches to fetal therapy. Project Narrative The overall goal of this translational project is to develop an understanding of cell-free nucleic acids as novel biomarkers of fetal development. Successful completion of the proposed work will significantly expand the current scope of prenatal diagnosis, resulting in tests that can find abnormalities in fetal gene expression. Genomic analysis in the proposed aims will lead to novel insights regarding fetal biological processes, which will result in entirely new approaches to fetal therapy.

项目概要目前的产前诊断和筛查方法涉及三种不同类型的检测：血清蛋白测量、超声检查胎儿成像和染色体分析。在这个我们建议通过了解以下应用，为胎儿评估增加一个新的维度无细胞核酸作为正常和异常胎儿功能发育的新型生物标志物不同的胎龄。在过去的四年里，这个领域呈指数级增长，涵盖了评估母血、羊水、脑脊液中的胎儿和胎盘 DNA 和 mRNA，和尿液。最近，利用母体胎儿游离 DNA 对胎儿恒河猴 D 状态进行无创诊断血液，已经从实验室过渡到床边。我们现在提出新的研究，该研究将建立在项目第 1-4 年的成就。在目标 1 中，我们将检验以下假设：游离 DNA（总 DNA 和胎儿）在妊娠期间具有生物学意义和临床应用。我们将检查临床胎儿性别检测在 X 连锁疾病、有先天性肾上腺增生风险的胎儿中的效用，以及生殖器不明确的胎儿。我们还将检查总无细胞水平的意义 DNA 作为组织缺氧和炎症的非侵入性标记。在目标 2 中，我们将检验假设可以使用无细胞技术区分正常和异常的胎儿基因表达母体体液（例如全血和羊水）中的 mRNA。我们的目标是开发一个面板区分正常和异常胎儿的关键基因，这将允许发育用于特定产前诊断应用的定制微阵列。在目标 3 中，我们将确定是否可以使用基因组方法更好地了解胎儿发育。使用现有软件包我们将分析目标 2 中获得的差异调节基因列表，以检查何时何地表达特定的胎儿基因。我们将确定参与正常的关键生物途径和胎儿发育异常，并受到胎儿治疗程序的影响。我们也将使用新的基因组方法，例如网络分析，可以理解复杂的生物关系。拟议实验计划的成功完成将显着扩大当前的范围解剖学、非整倍体和单基因疾病检测之外的产前诊断。基因组分析将带来对胎儿染色体和解剖异常的病理生理学的新见解，这最终将带来合理且全新的胎儿治疗方法。项目叙述该转化项目的总体目标是加深对无细胞核酸的理解：胎儿发育的新生物标志物。成功完成拟议工作将显着扩大目前产前诊断的范围，产生可以发现胎儿基因异常的测试表达。拟议目标中的基因组分析将带来有关胎儿生物学的新见解过程，这将带来全新的胎儿治疗方法。