Developmental effects of endometriosis on fertility of future generations

子宫内膜异位症对后代生育力的发育影响

• 批准号: 8890703
• 负责人: KATHY L TIMMS
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890703
• 关键词: Address; Animal Model; Characteristics; Chemicals; Chromatin; Clinic; Clinical; Critical Pathways; DNA Methylation; DNA Modification Process; Data; Development; Embryo; Embryonic Development; Epigenetic Process; Exposure to; Family; Female; Fertility; Functional disorder; Future Generations; Gene Expression; Generations; Genome; Germ Cells; Healthcare; Human; Infertility; Intervention; Knowledge; Laboratories; Lesion; Modeling; Molecular; Oocytes; Operative Surgical Procedures; Ovarian; Pathway interactions; Perinatal Exposure; Phenotype; Plant Roots; Pre-implantation Embryo Development; Prevention; Proteomics; Rattus; Reproductive Health; Reproductive Medicine; Symptoms; Testing; Therapeutic; Translating; Woman; base; blastocyst; endometriosis; epigenome; histone modification; imprint; knowledge translation; male; novel; novel therapeutic intervention; offspring; public health relevance; reproductive; safety testing; sex; sperm cell; transmission process

 DESCRIPTION (provided by applicant): Our long-term objective is to unravel mechanisms by which endometriosis causes infertility in females within families. The cause of reduced fecundity in endometriosis remains one of the greatest enigmas in reproductive medicine. Evidence supports an association between endometriosis and transgenerational infertility, yet the cause and effect relationship is unknown. This leads to billions of dollars spent annually on health care for symptom-driven, non-curative therapeutic approaches. This project will test the exploratory hypothesis that in utero exposure to endometriosis causes multigenerational reproductive anomalies in the offspring and reprogramming of gene expression in gametes and preimplantation embryos in three generations, which will translate into novel, unforeseen treatments to restore fertility in women with endometriosis. Specific Aim 1: Developmental (in utero) exposure to endometriosis of embryos or the embryo's embryonic germ cells manifests as abnormal litter and offspring characteristics, poor gamete quality and delayed/arrested embryo development in three generations of progeny from Endo vs. Control rats. Specific Aim 2: Subfertility in endometriosis is caused by molecular aberrations in DNA methylation and/or histone modifications of gametes (oocyte/sperm imprinting) and epigenetic DNA modifications and chromatin reorganization in embryos in a sex-specific manner thus altering gene expression pathways critical for gamete function and embryo development in three generations of Endo rats. Deciphering molecular mechanisms by which endometriosis disrupts fertility across multiple generations will facilitate discovery of prime targets for development of revolutionizing clinical interventions addressing the cause or even prevention of subfertility in women with endometriosis. These studies will be the first to determine whether multigenerational transmission causes alterations in embryo gene expression via the female and/or male. The significance to human reproductive health is enormous. These new interventions are paramount to evolve from surgical or chemical obliteration of lesions or repeated unsuccessful attempts at IVF. They also provide an avenue to test safety and efficacy of new paradigm changing clinical interventions and assist rapid translation of knowledge from the bench to the infertility clinic.

 描述（由申请人提供）：我们的长期目标是揭示子宫内膜异位症导致家庭女性不孕的机制子宫内膜异位症生育力降低的原因仍然是生殖医学中最大的谜团之一。跨代不孕症，但因果关系尚不清楚，这导致每年在医疗保健上花费数十亿美元。 该项目将测试探索性假设，即在子宫内暴露于子宫内膜异位症会导致后代出现多代生殖异常，并在三代中对配子和植入前胚胎的基因表达进行重新编程，这将转化为新的治疗方法。 ，恢复患有子宫内膜异位症的女性的生育能力的不可预见的治疗具体目标1：胚胎或胚胎的胚胎发育（在子宫内）暴露于子宫内膜异位症。 Endo 与对照大鼠的三代后代中，生殖细胞表现为异常的窝和后代特征、配子质量差以及胚胎发育延迟/停滞。 具体目标 2：子宫内膜异位症的生育力低下是由 DNA 甲基化和/或组蛋白的分子畸变引起的。配子修饰（卵母细胞/精子印记）以及胚胎中以性别特异性方式进行的表观遗传 DNA 修饰和染色质重组，从而改变对配子功能至关重要的基因表达途径破译子宫内膜异位症破坏多代生育能力的分子机制将有助于发现革命性临床干预措施的主要目标，以解决子宫内膜异位症女性生育力低下的原因，甚至预防这些研究。首次确定多代遗传是否会通过女性和/或男性导致胚胎基因表达的改变，这些新的干预措施对于通过手术或化学消除病变或重复不成功的尝试而发展起来至关重要。它们还提供了测试新范式改变临床干预措施的安全性和有效性的途径，并协助将知识从实验室快速转化为不孕不育诊所。