Preterm birth accounts for 75% of all perinatal deaths in the U.S. and can result in substantial morbidity in surviving infants. Despite a revolution in our appreciation of the genetic, molecular, cellular, and physiologic underpinnings of human biology, there has been little improvement in the rate of preterm birth over the last decade. The major goal of our application is to develop a theoretical framework and an analytic strategy for describing the complex interplay of genetic, physiological, and environmental factors in the mother and fetus that are related to preterm birth. Preterm birth is a """"""""complex trait"""""""" in that it has a multifactorial etiology that cannot be explained by independent variations in single genetic or environmental factors. Rather, a complex gestational trait like preterm birth involves an enormous array of interacting genes with multiple variable sites in both the mother and fetus, as well as interacting environmental factors that combine to produce the observed outcome. Standard statistical genetic models to predict quantitative phenotypic differences cannot accommodate the large number of variables in such systems. As such, descriptions of the genetic architecture of preterm birth require the development of novel theoretical models and analytic tools that consider the combinatorial effects of these many variable sites in the context of multiple environmental factors. In the proposed work, we will model the genetic architecture of the maternal-fetal neuroendocrine system, a prototypical physiological system that plays a central role in parturition. This model can be used to analyze the interrelationships among the genetic and environmental variables involved in any physiological system that links genetic and environmental causes to interindividual variation in the risk for preterm birth. This objective will be met through the following three specific aims: ? ? 1. Build a model bioinformatics resource describing the etiological components of the maternal-fetal neuroendocrine pathway. ? ? 2. Develop a generalized theoretical model describing the interactions among the genetic and environmental components of the maternal-fetal neuroendocrine system and their relationships to preterm birth. ? ? 3. Develop a statistical method for estimating the effect of maternal and fetal genes, gene-gene interactions, and gene-environment interactions on preterm birth in population based studies. ? ? This application is designed as a training vehicle for Dr. Vinod Misra to build upon his prior skills and experience in mathematical modeling in the physical sciences and to develop his expertise in a new field of study addressing the important problem of preterm birth. The grant provides support for both didactic and research training at the University of Michigan, a major research institution with a strong tradition in statistical genetics and genetic epidemiology. The educational climate and resources of the University, the commitment of his Department, and the expertise of his mentor will prepare Dr. Misra for a career as an independent investigator. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD045609-04
Application #
7274683
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Ilekis, John V
Project Start
2004-08-15
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$130,680
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Straughen, Jennifer K; Misra, Dawn P; Helmkamp, Laura et al. (2017) Preterm Delivery as a Unique Pathophysiologic State Characterized by Maternal Soluble FMS-Like Tyrosine Kinase 1 and Uterine Artery Resistance During Pregnancy: A Longitudinal Cohort Study. Reprod Sci 24:1583-1589
Misra, Vinod K; Straughen, Jennifer K; Trudeau, Sheri (2013) Maternal serum leptin during pregnancy and infant birth weight: the influence of maternal overweight and obesity. Obesity (Silver Spring) 21:1064-9
Straughen, Jennifer K; Misra, Dawn P; Kumar, Pawan et al. (2013) The influence of overweight and obesity on maternal soluble fms-like tyrosine kinase 1 and its relationship with leptin during pregnancy. Reprod Sci 20:269-75
Straughen, Jennifer K; Kumar, Pawan; Misra, Vinod K (2012) The effect of maternal soluble FMS-like tyrosine kinase 1 during pregnancy on risk of preterm delivery. J Matern Fetal Neonatal Med 25:1879-83
Bedoyan, Jirair K; Lesperance, Marci M; Ackley, Todd et al. (2011) A complex 6p25 rearrangement in a child with multiple epiphyseal dysplasia. Am J Med Genet A 155A:154-63
Misra, Vinod K; Trudeau, Sheri; Perni, Uma (2011) Maternal serum lipids during pregnancy and infant birth weight: the influence of prepregnancy BMI. Obesity (Silver Spring) 19:1476-81
Misra, Vinod K; Trudeau, Sheri (2011) The influence of overweight and obesity on longitudinal trends in maternal serum leptin levels during pregnancy. Obesity (Silver Spring) 19:416-21
Misra, Vinod K; Hobel, Calvin J; Sing, Charles F (2010) The effects of maternal weight gain patterns on term birth weight in African-American women. J Matern Fetal Neonatal Med 23:842-9
Vahratian, Anjel; Misra, Vinod K; Trudeau, Sheri et al. (2010) Prepregnancy body mass index and gestational age-dependent changes in lipid levels during pregnancy. Obstet Gynecol 116:107-13
Misra, V K; Hobel, C J; Sing, C F (2009) Placental blood flow and the risk of preterm delivery. Placenta 30:619-24

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