Systems biology approach to understand endometrial receptivity & pregnancy loss

描述（由申请人提供）：不孕不育是家畜和人类的主要问题。我们的长期目标是发现和了解调节子宫内膜着床接受性和子宫妊娠能力的激素，细胞和分子机制，以便为生育问题的诊断，预防和治疗提供有用的基础信息。受体子宫内膜代表了一个暂时的，但独特的生理状态的子宫，当受孕（胚胎和相关的胚胎外膜）生长和着床是可能的。子宫内膜容受性不足会影响胎儿生长、妊娠识别信号，并影响着床。子宫内膜容受性缺陷会导致家畜和人类的妊娠丢失，从而导致生育问题。本研究的目的是利用创新的大型动物模型结合系统生物学方法，更好地了解调节子宫内膜容受性和子宫能力的生物学和遗传机制，以建立和维持妊娠。为了实现这一目标，将在肉牛中进行胚胎的连续移植，以选择在早期妊娠损失方面存在内在差异的动物。选定的动物将被用于一系列的实验，以揭示控制子宫内膜容受性和妊娠成功的生理和遗传机制。具体目标是：(1)开发一种独特的动物资源，利用基于成功妊娠结局的肉牛生育能力的自然变化来研究子宫内膜容受性和妊娠损失；(2)研究子宫内膜容受性与妊娠丢失的生物学机制；(3)确定子宫内膜容受性和子宫妊娠能力的遗传机制。这项研究具有创新性，因为它将为子宫生物学和妊娠研究开发一种独特的动物模型。这项研究的完成有望通过对子宫内膜功能、不孕症和妊娠丢失提供新的见解来填补我们现有知识的实质性空白。该研究的转化结果包括子宫内膜容受性和子宫妊娠能力的生物标志物和选择工具。在畜牧业中，所鉴定的生物标志物有望提供诊断工具，以识别和选择子宫内膜容受性和妊娠成功率较高的小母牛，这将提高牛企业的生产效率和盈利能力。在生物医学领域，将已鉴定的生物标志物翻译到人类身上，应该提供子宫内膜容受性的新指标，可用于优化辅助生殖技术，诊断、治疗和预防不孕症和妊娠丢失。

DESCRIPTION (provided by applicant): Infertility and subfertility represent major problems in domestic animals and humans. Our long-range goal is to discover and understand the hormonal, cellular, and molecular mechanisms regulating endometrial receptivity to implantation and uterine competency for establishment of pregnancy in order to provide fundamental information useful for diagnosis, prevention and treatment of fertility problems. The receptive endometrium represents a temporary, but unique physiological state of the uterus when conceptus (embryo and associated extraembryonic membranes) growth and implantation is possible. Inadequate endometrial receptivity affects conceptus growth, signaling for pregnancy recognition, and compromises implantation. Defects in endometrial receptivity cause pregnancy loss and thus fertility problems in both domestic animals and humans. The goal of this proposal is to better understand the biological and genetic mechanisms regulating endometrial receptivity and uterine competency for establishment and maintenance of pregnancy using an innovative large animal model combined with a systems biology approach. To achieve this goal, serial transfer of embryos will be conducted in beef heifers to select animals with intrinsic differences in early pregnancy loss. The selected animals will then be used in a series of experiments to uncover the physiological and genetic mechanisms governing endometrial receptivity and pregnancy success. Specific aims are to: (1) develop a unique animal resource to study endometrial receptivity and pregnancy loss using natural variation in fertility of beef heifers based on successful pregnancy outcomes; (2) investigate biological mechanisms governing endometrial receptivity and pregnancy loss; and (3) determine genetic mechanisms underlying endometrial receptivity and uterine competency for pregnancy. This research is innovative, because it will develop a unique animal model for the study of uterine biology and pregnancy. Completion of the research is expected to fill a substantial gap in our existing knowledge by providing novel insights into endometrial function, infertility and pregnancy loss. Translational outcomes of the research include biomarkers and selection tools for endometrial receptivity and uterine competency for pregnancy. In animal agriculture, the identified biomarkers are expected to provide diagnostic tools to identify and select heifers with superior endometrial receptivity an pregnancy success, which will increase production efficiency and profitability of cattle enterprises. In biomedicine, translation of the identified biomarkers to humans should provide novel indicators of endometrial receptivity that can be used to optimize assisted reproduction techniques and to diagnose treat and prevent infertility and pregnancy loss. PUBLIC HEALTH RELEVANCE: This research is expected to provide a better understanding of origins of infertility and pregnancy loss and improve assisted reproduction efficiency in both humans and domestic animals. The research should lead to new therapies to enhance pregnancy outcome in females conceiving naturally or via assisted reproduction technologies (ART) and to diagnose, treat and prevent infertility and recurrent pregnancy loss. Consequently, this research proposal has a "dual benefit" for the improvement of health and reproduction in both humans and agriculturally important animals.