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Signaling mechanisms of gene-environment interactions in female reproductive

女性生殖基因-环境相互作用的信号机制

基本信息

批准号：
10594545
负责人：
YING XIA
金额：
$ 20.25万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594545
关键词：
Abdominal Pain Adult Affect Aryl Hydrocarbon Receptor Biological Process Cell Culture Techniques Cessation of life Childbirth Clinical Complex Congenital Abnormality Congenital Disorders Coupled Cyclic AMP-Dependent Protein Kinases Data Defect Development Developmental Toxicant Dioxins Disease Dose Embryo Environment Environmental Exposure Environmental Pollutants Environmental Risk Factor Epithelial Cells Epithelium Etiology Exposure to Female Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Diseases Genetic Risk Genetic study Goals Histology Human Immunohistochemistry Incidence Infertility Investigation Knockout Mice Knowledge Laboratories Left Link Live Birth MAP Kinase Gene MAP3K1 gene Mediating Menstruation Molecular Molecular Genetics Morphogenesis Mus Mutant Strains Mice Mutation Nature Pathway interactions Patients Periodicals Phenotype Pregnancy Puberty Regulation Reporter Repression Research Risk Severities Sexual Development Signal Pathway Signal Transduction Structure of paramesonephric duct Testing Tetrachlorodibenzodioxin Toxic effect Vagina WNT Signaling Pathway Women&apos s Health congenital anomaly developmental disease developmental toxicity experimental study falls gene environment interaction genetic approach genetic makeup genetic risk factor high risk human disease hymen in vivo laser capture microdissection loss of function mouse genetics mouse model mutant novel prenatal exposure prevent reproductive reproductive tract toxicant transcription factor transcriptome

项目摘要

Project Summary/Abstract Congenital anomalies of the female reproductive tract (FRT) occur in approximately 5% of live birth in females. These conditions are congenital, but often go undetected until puberty when the patients fail to menstruate and suffer periodic lower abdominal pain; if left untreated, they lead to infertility and death during pregnancy or childbirth. The anomalies have complex clinical presentations with the etiology still poorly understood. Given that FRT anomaly has both familial and sporadic cases, the causative agents are likely to be complex, involving genes, environmental factors, or both. To date, the multifactorial etiology and the mechanisms of gene- environment interactions in congenital FRT anomalies are largely unexplored. We have recently identified Map3k1 loss-of-function as a novel genetic condition of congenital FRT anomaly - Map3k1 inactivation in mice is associated with developmental FRT defects and infertility in females. Map3k1 encodes a protein kinase, an upstream regulator of the MAPK pathways that crosstalk with diverse environmental signals and developmental pathways. We have shown that Map3k1 loss-of-function could aggravate the developmental toxicity of dioxin, a ubiquitous environmental pollutant. Moreover, dioxin is also a reproductive toxicant that induces FRT defects similar to those observed in the Map3k1-null mice. In the current proposal, we will test the hypothesis, supported by preliminary evidence, that Map3k1 mutation plus dioxin constitute the multifactorial etiology that converges on WNT inhibition to cause congenital FRT anomalies. We will use an in vivo genetic approach to examine whether Map3k1 mutation plus dioxin exposure potentiate the incidence and/or the severity of FRT defective phenotypes, whether the dioxin receptor, Ah receptor (AHR), mediates FRT toxicity, and whether the gene- environment interactions repress WNT activity. We will combine mouse genetics, molecular histopathogenesis, and laser capture microdissection coupled with global gene expression profiling to delineate the biological processes and molecular pathways affected by genetic and environmental insults in FRT development. We aim to understand the molecular details of how gene-environment interactions contribute to congenital female reproductive anomaly, with the long-term future goal of using this knowledge to prevent and treat this prevalent devastating disease affecting women’s health and reproductivity.

项目总结/文摘