System biology approach to understand endometrial receptivity & pregnancy loss

了解子宫内膜容受性的系统生物学方法

• 批准号: 9128673
• 负责人: THOMAS E SPENCER
• 金额: $ 32.29万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128673
• 关键词: Accounting; Affect; Agriculture; Animal Model; Animals; Assisted Reproductive Technology; Biological; Biological Markers; Biology; Birth; Cattle; Collaborations; Competence; Complex; Conceptions; Conceptus; Country; DNA; DNA Sequence Rearrangement; Defect; Diagnosis; Diagnostic; Domestic Animals; Embryo; Embryo Transfer; Endometrial; Endometrium; Environment; European; Event; Female; Fertility; Fertilization in Vitro; Gene Expression; Genes; Genetic; Genomics; Goals; Growth; Health; Hormonal; Human; Inferior; Infertility; Knowledge; Lead; Membrane; Methods; Molecular; Outcomes Research; Ovarian; Pathway interactions; Physiological; Pregnancy; Pregnancy Maintenance; Pregnancy Outcome; Pregnancy Rate; Pregnancy loss; Prevention; Procedures; Production; Recurrence; Reproduction; Reproductive Biology; Reproductive Techniques; Research; Research Personnel; Research Proposals; Resources; Ruminants; Series; Signal Transduction; Staging; Systems Biology; Testing; Translations; United States; Uterus; Variant; animal resource; assisted reproduction; base; beef; biomarker selection; functional genomics; implantation; improved; infertility treatment; innovation; insight; multidisciplinary; novel; novel therapeutics; prevent; research study; success; tool; uterine receptivity

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.

描述（由申请人提供）：不孕不育和生育能力低下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容受性和子宫建立妊娠能力的激素、细胞和分子机制，以便为诊断、预防和治疗生育问题提供有用的基础信息。当概念（胚胎和相关的胚外膜）生长和植入可能时，接受性子宫内膜代表子宫的暂时但独特的生理状态。子宫内膜容受性不足会影响孕体生长、妊娠识别信号并影响着床。子宫内膜容受性缺陷会导致流产，从而导致家畜和人类的生育问题。该提案的目标是使用创新的大型动物模型与系统生物学方法相结合，更好地了解调节子宫内膜容受性和子宫能力以建立和维持妊娠的生物学和遗传机制。为了实现这一目标，将在肉牛中进行胚胎连续移植，以选择在早期妊娠损失方面具有内在差异的动物。然后，选定的动物将用于一系列实验，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。具体目标是：（1）开发独特的动物资源，利用基于成功妊娠结果的小母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) 研究控制子宫内膜容受性和流产的生物学机制； (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，因为它将开发一种独特的动物模型来研究子宫生物学和妊娠。该研究的完成预计将通过提供关于子宫内膜功能、不孕症和流产的新见解来填补我们现有知识的巨大空白。该研究的转化成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来识别和选择具有优越子宫内膜容受性并成功妊娠的小母牛，这将提高养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转化为人类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以及诊断、治疗和预防不孕症和流产。

项目成果

Conceptus-derived prostaglandins regulate gene expression in the endometrium prior to pregnancy recognition in ruminants.

• DOI: 10.1530/rep-13-0165
• 发表时间: 2013-10
• 期刊: Reproduction (Cambridge, England)
• 作者: Spencer TE;Forde N;Dorniak P;Hansen TR;Romero JJ;Lonergan P
• 通讯作者: Lonergan P

Analysis of the uterine lumen in fertility-classified heifers: II. Proteins and metabolites

• DOI: 10.1093/biolre/ioz197
• 发表时间: 2020-03-01
• 期刊: BIOLOGY OF REPRODUCTION
• 影响因子: 3.6
• 作者: Moraes, Joao G. N.;Behura, Susanta K.;Spencer, Thomas E.
• 通讯作者: Spencer, Thomas E.

Oviduct-Embryo Interactions in Cattle: Two-Way Traffic or a One-Way Street?

• DOI: 10.1095/biolreprod.115.127969
• 发表时间: 2015-06-01
• 期刊: BIOLOGY OF REPRODUCTION
• 影响因子: 3.6
• 作者: Maillo, Veronica;Gaora, Peadar O.;Rizos, Dimitrios
• 通讯作者: Rizos, Dimitrios

Loci and pathways associated with uterine capacity for pregnancy and fertility in beef cattle.

• DOI: 10.1371/journal.pone.0188997
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Neupane M;Geary TW;Kiser JN;Burns GW;Hansen PJ;Spencer TE;Neibergs HL
• 通讯作者: Neibergs HL

Identification of Beef Heifers with Superior Uterine Capacity for Pregnancy.

• DOI: 10.1095/biolreprod.116.141390
• 发表时间: 2016-08
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Geary TW;Burns GW;Moraes JG;Moss JI;Denicol AC;Dobbs KB;Ortega MS;Hansen PJ;Wehrman ME;Neibergs H;O'Neil E;Behura S;Spencer TE
• 通讯作者: Spencer TE