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The Pharmacoepigenomics of Recurrent Preterm Birth in Non-Hispanic Black Women

非西班牙裔黑人女性反复早产的药物表观基因组学

基本信息

批准号：
9540949
负责人：
TRACY A. MANUCK
金额：
$ 76.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-08 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9540949
关键词：
37 weeks gestation Acute Biology Blood Caproates Clinical DNA Methylation Data Development Diagnostic tests Enrollment Epigenetic Process Fetal Tissues Functional disorder Gene Expression Gene Expression Profile Genes Genotype Goals High Risk Woman Hydroxyprogesterone Hypermethylation Infant Infection Inflammation Intervention Trial Intramuscular Knowledge Lead Light Literature Lymphocyte Measures Mediating Medical Methylation Mission Modeling Morbidity - disease rate Mothers Muscle relaxants Myometrial NOS2A gene Neonatal Mortality Nitric Oxide Nitric Oxide Donors Nitric Oxide Pathway Nitric Oxide Signaling Pathway Nitroglycerin Not Hispanic or Latino Outcome Pathway interactions Pattern Pharmaceutical Preparations Population Pregnancy Premature Birth Prevention Progesterone Prophylactic treatment Proteomics Psychosocial Stress Public Health Publishing Race Recording of previous events Recurrence Relaxation Research Research Infrastructure Risk Risk Factors Risk stratification Role Sampling Second Pregnancy Trimester Site Smooth Muscle Stimulus Survivors Synthetic Progestogens Testing Therapeutic Agents Tissues Treatment Failure Umbilical Cord Blood Variant Woman Women&apos s Group Work base biobank clinical risk differential expression disability disparity reduction epigenetic marker fetal gene conservation high risk innovation insight mRNA Differential Displays macrophage mortality myometrium neonate neutrophil novel offspring prevent racial disparity recruit response social standard of care uterine contractility

项目摘要

PROJECT SUMMARY There is a critical gap in our understanding of mechanisms that underlie spontaneous preterm birth (SPTB) in non-Hispanic (NH) black women. Preterm delivery (<37 weeks gestation) is the leading cause of mortality among non-anomalous neonates; survivors are at increased risk for lifelong intellectual, physical, and social disabilities compared with their term counterparts. NH black women are twice as likely as women of other races to deliver preterm. 17-alpha hydroxyprogesterone caproate (17P) prevents recurrent SPTB in some women, but is less effective for NH black compared with NH white women. The reasons for this variable responsiveness are poorly understood, and represent a critical knowledge gap. The long-term goal of this research is to identify NH black women at risk for 17P non-response, provide them with alternate therapies, and thereby reduce the risk of recurrent SPTB. The objective here is to quantify the role of nitric oxide (NO) pathways in the pathophysiology of recurrent SPTB among NH black women receiving 17P. Our central hypothesis is that aberrations in the NO pathway predispose NH black women to 17P non-response for the recurrent SPTB prevention. This hypothesis is based on our preliminary data and published literature showing maternal genotype, maternal blood-derived and placental-derived proteomic profiles, and DNA methylation in the NO pathway differ among women destined to be 17P non-responders. Furthermore, our studies show strong race-disparity in NO pathway genes. The rationale for this work is that it will provide new insight and increased understanding into the pathophysiology and biologic mechanisms of non-response to 17P for SPTB prevention among NH black women, a group at disproportionately high risk of 17P treatment failure. The central hypothesis will be tested by pursuing three Aims: (1) Determine which genes in the NO pathway are differentially expressed in the mid-trimester among women destined to be 17P non-responders, (2) Establish which NO pathway genes display differential CpG methylation in the mid-trimester in 17P non-responders, and (3) Quantify conservation of gene expression and epigenetic markers between mother and offspring. These aims will be assessed using longitudinal samples from 300 NH black women. This approach is innovative, because this project will examine epigenetic and expression changes in maternal circulating blood and in fetal- derived tissues in response to 17P, shedding light on acute changes that occur in response to 17P. The proposed research is significant because as methylation and gene expression patterns are recognizable in the second trimester, they may provide the basis for development of diagnostic tests to identify women at risk for recurrent PTB despite 17P prophylaxis. This project is directly aligned with the mission of the NIMHD, and will provide immediate and sustained clinical and public health impact to reduce disparities in PTB outcomes in NH black women and infants, thereby reducing neonatal mortality and lifelong morbidity.

项目总结