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：
7993056
负责人：
DIANA W. BIANCHI
金额：
$ 32.52万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7993056
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 First Pregnancy Trimester Functional disorder Gastroschisis Gender Gene Expression Genes Genitalia Genomics Gestational Age Goals Growth Health Hypoxia Image Inflammation Lead Link Macaca mulatta Measurement Messenger RNA Meta-Analysis Nucleic Acids Pathway Analysis Pathway interactions Plasma Pregnancy Pregnancy Complications Prenatal Diagnosis Procedures Protein Analysis RNA 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：目前的产前诊断和筛查手段涉及三种不同类型的测定：血清蛋白测量、通过超声检查进行胎儿成像以及染色体分析。在此应用中，我们建议通过加深对无细胞核酸作为不同胎龄胎儿正常和异常功能发育的新生物标志物的理解，为胎儿评估增加一个新的维度。在过去的四年里，这一领域呈指数级扩展，涵盖了母血、羊水、脑脊液和尿液中胎儿和胎盘 DNA 和 mRNA 的评估。最近，利用母体血液中的胎儿游离 DNA 对胎儿恒河猴 D 状态进行无创诊断已从实验室过渡到临床。我们现在提出新的研究，这些研究将建立在项目第 1-4 年成果的基础上。在目标 1 中，我们将检验以下假设：游离 DNA（总 DNA 和胎儿 DNA）在妊娠期间具有生物学意义和临床应用。我们将研究胎儿性别检测在 X 连锁情况、有先天性肾上腺增生风险的胎儿以及生殖器不明确的胎儿中的临床效用。我们还将研究总游离 DNA 水平作为组织缺氧和炎症的非侵入性标志物的重要性。在目标 2 中，我们将测试以下假设：可以使用全血和羊水等母体体液中的无细胞 mRNA 来区分正常和异常的胎儿基因表达。我们的目标是开发一组区分正常和异常胎儿的关键基因，这将允许开发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来更好地了解胎儿发育。使用现有的软件包，我们将分析目标 2 中获得的差异调节基因列表，以检查特定胎儿基因表达的地点和时间。我们将确定涉及正常和异常胎儿发育以及受胎儿治疗程序影响的关键生物学途径。我们还将使用新的基因组方法（例如网络分析）来理解复杂的生物关系。所提出的实验计划的成功完成将显着扩大当前产前诊断的范围，超越解剖学、非整倍体和单基因疾病检测。基因组分析将为胎儿染色体和解剖异常的病理生理学带来新的见解，这最终将带来合理且全新的胎儿治疗方法。公共健康相关性：该转化项目的总体目标是加深对无细胞核酸作为胎儿发育的新型生物标志物的理解。成功完成拟议的工作将显着扩大当前产前诊断的范围，从而产生可以发现胎儿基因表达异常的测试。拟议目标中的基因组分析将带来关于胎儿生物学过程的新见解，这将带来全新的胎儿治疗方法。