Embryotropic actions of follistatin: mechanisms and translational relevance

卵泡抑素的胚胎亲性作用：机制和转化相关性

• 批准号: 8335579
• 负责人: Jason Glenn Knott
• 金额: $ 31.85万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-27 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335579
• 关键词: Ablation; Activins; Address; Assisted Reproductive Technology; Binding; Binding Proteins; Biotechnology; Blastocyst Transfer; Cattle; Cell Count; Cells; Clinical; Cloning; Comparative Study; Competence; Data; Development; Distress; Early treatment; Embryo; Embryo Transfer; Embryonic Development; Endocrine; Epigenetic Process; Experimental Models; Failure; Female; Fertilization; Follistatin; Foundations; Functional disorder; Gene Expression Profile; Genes; Genetic; Goals; Growth Factor; Health; Human; In Vitro; Infertility; Knowledge; Life; Ligands; Macaca mulatta; Maternal Age; Measurement; Mediating; Mediator of activation protein; Modeling; Molecular; Oocytes; Ovarian; Pathway interactions; Patients; Physiology; Placentation; Plague; Pregnancy; Pregnancy Rate; Procedures; Production; Protein Analysis; Publishing; RNA analysis; Receptor Serine/Threonine Kinase; Research; Role; Safety; Signal Transduction; Signal Transduction Pathway; Solid; Staging; Technology; Therapeutic; Therapeutic Intervention; Time; Translating; Woman; blastocyst; clinically relevant; egg; embryo culture; female reproductive system; fundamental research; improved; indexing; member; nuclear transfer; overexpression; poor egg quality; preimplantation; programs; reproductive; research study; somatic cell nuclear transfer; success; tool

DESCRIPTION (provided by applicant): Infertility is a distressing human health concern with a large proportion of cases attributed, at least in part, to dysfunction of the female reproductive system and specifically to reduced oocyte quality. As a result, patients often turn to costly assisted reproductive technologies (ART), with over 2 billion dollars spent annually on ART procedures in the US and failure ~ 69% of the time. Much needed improvements in the efficacy and safety of ART are limited by a dearth of fundamental knowledge of the intracellular and intercellular mechanisms and mediators of oocyte quality. The studies proposed here build upon a solid foundation of published data demonstrating a positive association of oocyte expression of the TGFb superfamily binding protein follistatin with bovine oocyte quality and a functional role for follistatin in promoting enhanced development of in vitro fertilized bovine embryos to blastocyst stage and blastocyst cell allocation to trophectoderm. Comparative studies using rhesus monkey embryos also support similar tropic actions of follistatin on embryonic development to blastocyst stage. However, lack of understanding of mechanism of action of follistatin in mediating above embryotropic actions and impact of follistatin treatment during embryo culture on pregnancy rates following embryo transfer limit understanding of the functional significance of follistatin to early embryogenesis and the translational relevance of above findings to improvements in human ART and biomedically relevant biotechnologies such as nuclear transfer/cloning in bovine species. Studies in Aim 1 will utilize a combination of pharmacological approaches, ablation replacement strategies and overexpression procedures in early embryos, combined with traditional RNA and protein analysis and analysis of epigenetic marks on key trophectoderm expressed genes to determine the mechanism of action of follistatin in promoting enhanced blastocyst development, blastocyst cell allocation to trophectoderm and interactions with specific TGFb superfamily members and their signal transduction pathways. Furthermore, deficiencies in extraembryonic lineage are common in pregnancies from nuclear transfer embryos and preliminary results demonstrate potent stimulatory effects of follistatin on nuclear transfer embryo blastocyst development and cell allocation to trophectoderm. In Aim 2, the translational relevance of follistatin treatment as a tol to enhance ART will be determined via measurement of pregnancy rates and placental development for follistatin treated in vitro fertilized and nuclear transfer bovine embryos following embryo transfer and impact of follistatin treatment on epigenetic reprogramming of developmentally significant trophectoderm expressed genes examined. Upon completion of proposed studies, a better understanding of potential mechanism of action of follistatin and additional targets for therapeutic intervention will be known and the translational relevance of follistatin treatment during in vitro embryo culture as a tool to enhance ART and nuclear transfer pregnancy rates further elucidated. PUBLIC HEALTH RELEVANCE: Improvements in the efficacy and safety of assisted reproductive technologies (ART) utilized for treatment of infertility are limited by a dearth of fundamental knowledge of the mechanisms and mediators of oocyte (egg) quality. We are studying the intrinsic role and mechanism of action of follistatin in enhancing progression through early embryonic development and whether follistatin treatment of early bovine embryos can enhance pregnancy rates following embryo transfer. Such information is critical to potential application of follistatin treatment as a tool to enhance human ART and biomedically relevant embryo biotechnologies in cattle.

描述（由申请人提供）：不孕症是令人痛苦的人类健康问题，其中很大一部分归因于女性生殖系统功能障碍，特别是降低了卵母细胞质量。 结果，患者通常会转向昂贵的辅助生殖技术（ART），每年在美国的艺术程序上花费了超过20亿美元，而失败的时间约为69％。由于缺乏细胞内和细胞间机制和卵母细胞质量的介体的基本知识，因此急需改善艺术的功效和安全性的限制。此处提出的研究基于已发表的数据的坚实基础，表明TGFB超家族结合蛋白的卵母细胞表达与牛卵母细胞质量和卵泡蛋白在促进促进体外牛油胚胎促进胚泡级别的胚胎胚胎胚胎胚层和胚泡细胞分配方面的发育方面的功能作用。使用恒河猴胚胎的比较研究还支持卵泡素对胚胎发育与胚泡阶段的类似热带作用。然而，缺乏对卵泡素在介导的胚胎作用中的作用机理的理解，以及胚胎培养过程中卵泡素治疗对胚胎转移限制对卵泡素对早期胚胎发生的功能意义的理解后，对早期胚胎的功能意义的影响以及上述对人类艺术和生物学相关的转化型的转化性转化。目标1中的研究将利用早期胚胎中的药理学方法，消融替换策略和过表达程序的结合，结合传统的RNA和蛋白质分析以及对关键的滋养剂表达基因的表观遗传标记的分析，以确定folltistin在促进促进型细胞中的效应机能的机能，并确定促进囊肿的囊泡囊肿，并促进胚泡的囊泡囊泡的效果。成员及其信号转导途径。此外，核转移胚胎的怀孕期间常见于胚外谱系的缺乏，初步结果表明，卵泡素对核转移胚胎胚泡的发育和细胞分配给滋养剂的刺激作用。在AIM 2中，将通过测量妊娠率和胎盘发育来确定Follistatin治疗作为增强艺术的转化相关性，用于在胚胎转移后接受体外受精和核转移牛胚胎的卵泡素的胎盘发育，以及在卵泡素治疗对表观遗传学上的表观遗传重新编写的良大滋养型滋养基因研究的表达良好的基因审查的表达明确的基因研究。在完成拟议的研究完成后，将知道对卵泡素作用机理的更好理解和治疗干预的其他靶标，并且在体外胚胎培养过程中卵泡蛋白治疗的转化相关性将作为增强艺术和核转移妊娠率的工具进一步阐明。 公共卫生相关性：用于治疗不育治疗的辅助生殖技术（ART）的功效和安全性的改善受到对卵母细胞（Egg）质量机制和介体的基本知识的限制。我们正在研究卵泡素通过早期胚胎发育增强进展的内在作用和作用机制，以及卵泡素对早期牛胚胎的治疗是否可以在胚胎转移后提高妊娠率。这些信息对于卵泡治疗作为增强人类艺术和牛与生物医学相关的胚胎生物技术的工具至关重要。