Systems biology approach to understand endometrial receptivity & pregnancy loss

描述(申请人提供)：不孕不育和亚生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能力和子宫受孕能力的激素、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。接受型子宫内膜代表着一种暂时但独特的子宫生理状态，此时受孕(胚胎和相关的胚胎外膜)的生长和着床是可能的。子宫内膜容受性不足会影响胚胎的发育，发出识别妊娠的信号，并影响着床。子宫内膜容受性缺陷会导致妊娠丢失，从而导致家畜和人类的生育问题。这项建议的目的是利用创新的大型动物模型和系统生物学方法，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学机制，以建立和维持妊娠。为了实现这一目标，将在小母牛身上进行胚胎的连续移植，以选择在早孕丢失方面存在内在差异的动物。然后，选定的动物将被用于一系列实验，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。具体目的是：(1)开发独特的动物资源，以成功妊娠结局为基础，利用小母牛生育力的自然变化来研究子宫内膜容受性和妊娠丢失；(2)研究子宫内膜容受性和妊娠丢失的生物学机制；以及(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填补我们现有知识的一个重大空白，为子宫内膜功能、不孕不育和妊娠丢失提供新的见解。这项研究的翻译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，识别出的生物标志物有望提供诊断工具，以识别和选择具有良好子宫内膜容受性和妊娠成功的小母牛，这将提高牛企业的生产效率和盈利能力。在生物医学中，将已识别的生物标志物翻译到人类身上，将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。 公共卫生相关性：这项研究有望更好地了解不孕不育和妊娠丢失的原因，并提高人类和家畜的辅助生殖效率。这项研究应该导致新的治疗方法，以提高自然怀孕或通过辅助生殖技术(ART)怀孕的女性的妊娠结局，并诊断、治疗和预防不孕不育和反复妊娠丢失。因此，这项研究建议对改善人类和农业上重要动物的健康和生殖都有“双重好处”。

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.