Fetal growth restriction (FOR), a term used to define all fetuses that are below the 10th percentile in weight at a given gestational stage, is a complex, pleiotropic disorder. FOR is an ethnic health disparity in the United States and is associated with substantially elevated newborn mortality and morbidity. While there are many risk factors for FGR, the molecular and cellular mechanisms that are involved in FGR are poorly understood. The long term goal of this study is to identify and understand the molecular and cellular mechanisms associated with FGR, which in turn could lead to both novel means of therapeutic intervention as well as new methods for early diagnosis and prognosis. Telomerase is an enzymatic complex that is required to prevent cell senescence by completing the replication and preventing the erosion of chromosomal ends (telomeres) in dividing cells. Telomerase activity is present throughout gestation in the human placenta, but is higher during early perinatal development than later. Furthermore, it has recently been demonstrated that telomerase activity is suppressed in the placenta of asymmetric cases of FGR. Our specific hypothesis is that telomerase defects underlie many cases of idiopathic FGR, especially those with accelerated placental maturation. To assess this hypothesis, we propose 3 specific aims: 1) Establish a modern and comprehensive characterization of FGR using clinical data, anthropometric assessment, and molecular techniques for known etiologies, """"""""Phenotype"""""""" idiopathic cases to allow appropriate comparisons, and describe which subcategories are responsible for health disparities in ethnic minorities. 2) Assess the role of telomerase suppression and accelerated telomere shortening in the placenta as a potential cause of fetal growth restriction in one or more ethnic groups. We will collect placental tissue and cord blood for neonates diagnosed with FGR and analyse, using various molecular techniques, telomere length, telomerase activity, and the expression of the RNA component of telomerase {TR} and the catalytic component of telomerase, telomerase reverse transcriptase (TERT) in placental tissue. In those cases in which suppression of telomerase activity in the placenta is observed, we will search for polymorphisms/mutations in the TR gene and TERT gene as well as several candidate TERT regulatory genes. 3) Screen for other genes underlying idiopathic cases of FGR by genotype analysis of single nucleotide polymorphisms.
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