Feto-maternal DNA/RNA Trafficking: Biology and Application

胎儿-母体 DNA/RNA 贩运：生物学和应用

• 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
• 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

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.

项目摘要 目前的产前诊断和筛查手段涉及三种不同类型的化验： 血清蛋白质测量、超声胎儿成像和染色体分析。在这 应用我们建议通过发展对胎儿评估的理解来为胎儿评估增加一个新的维度 无细胞核酸作为胎儿功能发育正常和异常的新生物标志物 不同的孕龄。在过去的四年里，这一领域呈指数级增长，包括 孕妇血、羊水、脑脊液中胎儿和胎盘DNA及mRNA的检测 还有尿液。最近，利用孕妇外周血中无细胞胎儿DNA无创性诊断胎儿恒河猴D状态。 血，已经从板凳过渡到了床边。我们现在提出新的研究，这些研究将建立在 项目第1-4年取得的成绩。在目标1中，我们将测试无细胞DNA(总DNA和 胎儿)在孕期具有生物学意义和临床应用价值。我们将检查临床 X-连锁条件下胎儿性别检测在先天性肾上腺增生症风险胎儿中的应用 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志物。在目标2中，我们将检验假设 使用无细胞技术可以区分正常和异常的胎儿基因表达 母体体液，如全血和羊水中的mRNA。我们的目标是开发一款 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，我们将确定一个 可以使用基因组方法来更好地了解胎儿的发育。使用现有的软件包 我们将分析在目标2中获得的差异调控基因列表，以检查何时何地 特定的胎儿基因被表达出来。我们将确定参与正常的关键生物通路 和胎儿发育异常，并受到胎儿治疗程序的影响。我们还将使用新的 基因组学方法，如网络分析，以了解复杂的生物关系。 拟议的试验计划的成功完成将大大扩大目前的范围 超越解剖学、非整倍体和单基因紊乱检测的产前诊断。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， 这最终将导致理性的和全新的胎儿治疗方法。项目叙事 这个翻译项目的总体目标是发展对无细胞核酸的理解，如 胎儿发育的新生物标志物。拟议工作的圆满完成将大大 扩大目前产前诊断的范围，推出可以发现胎儿基因异常的测试 表情。拟议目标中的基因组分析将导致对胎儿生物学的新见解 这将为胎儿治疗带来全新的方法。