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.

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042053-10
Application #
8390457
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Urv, Tiina K
Project Start
2002-04-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2013
Total Cost
$308,573
Indirect Cost
$116,913
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Edlow, Andrea G; Vora, Neeta L; Hui, Lisa et al. (2014) Maternal obesity affects fetal neurodevelopmental and metabolic gene expression: a pilot study. PLoS One 9:e88661
Massingham, Lauren J; Johnson, Kirby L; Scholl, Thomas M et al. (2014) Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome. Hum Genet 133:1075-82
Zwemer, Lillian M; Hui, Lisa; Wick, Heather C et al. (2014) RNA-Seq and expression microarray highlight different aspects of the fetal amniotic fluid transcriptome. Prenat Diagn 34:1006-14
Hui, Lisa; Bianchi, Diana W (2013) Recent advances in the prenatal interrogation of the human fetal genome. Trends Genet 29:84-91
Hui, Lisa; Wick, Heather C; Edlow, Andrea G et al. (2013) Global gene expression analysis of term amniotic fluid cell-free fetal RNA. Obstet Gynecol 121:1248-54
Hui, Lisa; Wick, Heather C; Moise Jr, Kenneth J et al. (2013) Global gene expression analysis of amniotic fluid cell-free RNA from recipient twins with twin-twin transfusion syndrome. Prenat Diagn 33:873-83
Hui, Lisa; Slonim, Donna K; Wick, Heather C et al. (2012) The amniotic fluid transcriptome: a source of novel information about human fetal development. Obstet Gynecol 119:111-8
Dietz, Jessica A; Johnson, Kirby L; Massingham, Lauren J et al. (2011) Comparison of extraction techniques for amniotic fluid supernatant demonstrates improved yield of cell-free fetal RNA. Prenat Diagn 31:598-9
Bianchi, Diana W (2011) Gene expression analysis of amniotic fluid: new biomarkers and novel antenatal treatments. Clin Biochem 44:448-50
Massingham, Lauren J; Johnson, Kirby L; Bianchi, Diana W et al. (2011) Proof of concept study to assess fetal gene expression in amniotic fluid by nanoarray PCR. J Mol Diagn 13:565-70

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