Sexual dimorphism in developmental programming caused by CSF2

CSF2 引起的发育程序中的性别二态性

基本信息

批准号：
9360210
负责人：
Peter J. Hansen
金额：
$ 35.03万
依托单位：
UNIVERSITY OF FLORIDA
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：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360210
关键词：
Adult Animal Feed Animals Cattle Characteristics Colony-Stimulating Factors Competence DNA Methylation Data Development Embryo Embryonic Development Endometrium Environment Exposure to Female Fertilization in Vitro Food Gene Expression Goals Growth Health Health Food Human In Vitro Inflammation Knock-out Laboratories Lactation Lead Life Livestock Mammalian Oviducts Mediating Methods Modification Morphology Morula Mothers Mus Newborn Animals Outcome Phenotype Pregnancy Pregnancy loss Procedures Process Production Productivity Program Development Protein-Restricted Diet Research Risk Sex Characteristics Shapes Signal Transduction Signaling Molecule Somatotropin Testing Woman adverse outcome blastocyst experimental study fertility improvement improved in utero in vivo male methylome milk production novel strategies offspring postnatal preimplantation programs receptor response sex sexual dimorphism success

项目摘要

PROJECT SUMMARY The developmental program of the preimplantation embryo is modified by alterations in its microenvironment. The resultant change in development can have long-acting effects that extend into postnatal life. Inappropriate signaling between mother and embryo can lead to increased pregnancy loss and long-term changes in health. Research on developmental programming could lead to elimination of adverse outcomes associated with IVF and result in new approaches to improve human health and animal production generally. One characteristic of developmental programming during the preimplantation period is sexual dimorphism in the modification in adult phenotype. Sex differences in embryonic responses to changes in the microenvironment are likely mediated in part by sex-specific responses of the embryo to maternal regulatory signals. One molecule involved in this phenomenon is colony stimulating factor 2 (CSF2). In cattle, treatment of morula and blastocyst stage embryos with CSF2 changed embryonic characteristics at a later point in pregnancy (Day 15) in a sex-specific manner and, at least in female offspring, resulted in calves with increased growth rates in the first year of life. The long-term goal is to understand how the microenvironment of the embryo interacts with sex to shape the developmental program. The overall objectives of the current proposal are to 1) elucidate mechanisms by which CSF2 causes differential programming actions on male and female embryos and 2) characterize the consequences of actions of CSF2 on the preimplantation embryo in vitro and in vivo for subsequent embryonic and postnatal phenotype. It is hypothesized that sex-dependent responses to CSF2 depend upon differences between male and female embryos in remodeling of DNA methylation by CSF2 and that these changes in DNA methylation result in long-acting effects on the developmental program that have consequences for postnatal phenotype. There are three specific aims. For Aim 1, it will be tested whether differences between male and female preimplantation embryos in programming actions of CSF2 on the Day 15 embryo are dependent upon DNA methylation. For Aim 2, the importance of CSF2 for embryonic development in vivo will be evaluated by testing consequences of knocking out the CSF2 receptor for embryo elongation, gene expression and DNA methylation in male and female embryos. Aim 3 will focus on ascertaining whether exposure of the preimplantation female embryo to CSF2 programs development to alter postnatal phenotype in a manner that improves dairy cow productivity. Through these aims, we will elucidate importance of remodeling of the methylome for sex-dependent actions of CSF2 (Aims 1) and ascertain whether actions of CSF2 occur not only in vitro but also for embryos developing in utero (Aim 2). Finally, the experiment for Aim 3 represents the first attempt to enhance productivity of a food animal through use of a developmental programming molecule to manipulate development in the preimplantation period. .

项目概要植入前胚胎的发育程序通过其微环境的改变而改变。由此产生的发育变化可能会产生长期影响，并延续到出生后的生活。不当母亲和胚胎之间的信号传导可能导致流产增加和健康的长期变化。对发展规划的研究可能会导致消除相关的不良后果体外受精（IVF）并带来改善人类健康和动物生产的新方法。一植入前时期发育规划的特征是性别二态性成人表型的改变。胚胎对微环境变化反应的性别差异可能部分是由胚胎对母体调节信号的性别特异性反应介导的。一参与这种现象的分子是集落刺激因子2 (CSF2)。在牛中，治疗桑葚和含有 CSF2 的囊胚期胚胎在妊娠后期（第 15 天）改变了胚胎特征以特定性别的方式，至少在雌性后代中，导致小牛的生长速度加快生命的第一年。长期目标是了解胚胎的微环境如何与胚胎相互作用性来塑造发育计划。当前提案的总体目标是 1) 阐明 CSF2 对雄性和雌性胚胎产生差异编程作用的机制以及 2) 描述 CSF2 在体外和体内对植入前胚胎的作用后果随后的胚胎和出生后表型。据推测，对 CSF2 的性别依赖性反应取决于男性和女性胚胎在 CSF2 重塑 DNA 甲基化方面的差异 DNA 甲基化的这些变化会对发育程序产生长期影响产后表型的后果。具体目标有三个。对于目标 1，将测试是否男性和女性植入前胚胎在第 15 天 CSF2 编程行为的差异胚胎依赖于DNA甲基化。对于目标 2，CSF2 对胚胎发育的重要性体内将通过测试敲除 CSF2 受体对胚胎伸长的影响来评估，男性和女性胚胎中的基因表达和 DNA 甲基化。目标 3 将重点确定是否将植入前雌性胚胎暴露于 CSF2 程序开发中以改变产后表型一种提高奶牛生产力的方法。通过这些目标，我们将阐明重塑的重要性确定 CSF2 性别依赖性作用的甲基化组（目标 1）并确定 CSF2 的作用是否发生不仅适用于体外，还适用于子宫内发育的胚胎（目标 2）。最后，目标 3 的实验代表通过使用发育规划来提高食用动物生产力的首次尝试控制植入前发育的分子。。