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Placental models to support embryogenesis in vitro

支持体外胚胎发生的胎盘模型

基本信息

批准号：
10458580
负责人：
Magdalena Zernicka-Goetz
金额：
$ 116.55万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-07-31
项目状态：
未结题

项目摘要

Most human pregnancies fail around the time of embryo implantation. Yet, the developmental mechanisms of this stage and how they go awry remain a mystery, because the implanted embryo is inaccessible to analysis within the body of the mother. Uncovering these mechanisms is of critical importance to overcome existing barriers to fertility and proper development. We have successfully generated systems that enable development of natural mouse and human embryos from pre- to post-implantation stages in vitro, and built stem cell-derived synthetic mouse embryos that can mimic some aspects of early post-implantation development. But approaches to study development continuously through the implantation stage and beyond gastrulation are lacking. We now propose to create a maternal-like environment that permits the long-term survival of both natural and synthetic mouse embryos. Our first challenge will be to engineer synthetic pre-implantation blastocysts with an expanded ability to generate the full range of correctly functioning extra-embryonic tissues. This breakthrough is expected to enable their implantation and development in utero, and may eventually transform approaches for engineering genetically modified mice. We will use these new tools to determine the precise cellular and molecular mechanisms that allow synthetic blastocysts to interact with the uterus in foster mothers. Our second challenge will be to generate artificial substrates, comprising hydrogels and proteins of the decidual extra-cellular matrix, to facilitate implantation events. In parallel, we will engineer synthetic placental-like structures for natural and synthetic embryo development using organoids derived from trophoblast and endometrial tissue. These systems would allow investigations and tracking of how insults to pre- and peri-implantation development, such as the exposure to pathogens, toxins, or teratogens affect subsequent development and life. Our third challenge will be to utilize these systems to discover the molecular events that accompany implantation. We will take advantage of our in vitro placental systems to investigate the chemical and physical signalling events that are key for development and determine how improved extra-embryonic contributions affect embryonic development until neurulation. These innovations will allow us to finally decipher a stage of development that is currently out of reach and of which our knowledge is greatly lacking. This will bring insight into a time of development when most pregnancies fail and thereby lead to advances in assisted reproductive technology; it will offer new screening routes for drug testing and environmental safety; and it will advance our knowledge of the use of stem cells in organogenesis and regenerative medicine.

大多数人类妊娠在胚胎植入时失败。然而，发展机制这一阶段以及它们是如何出错的仍然是一个谜，因为植入的胚胎是无法进入的。在母亲体内的分析。揭示这些机制对于克服生育和适当发展的现有障碍。我们已经成功地建立了系统，在体外从植入前到植入后阶段发育天然小鼠和人胚胎，并构建干细胞衍生的合成小鼠胚胎，可以模拟植入后早期的某些方面，发展但是，通过植入阶段持续研究发育的方法，除了原肠胚形成之外，我们现在建议创造一个母亲般的环境，天然和合成小鼠胚胎的长期存活。我们的第一个挑战是合成的植入前胚泡，具有产生全方位正确发育的能力，功能性胚胎外组织这一突破有望使它们的植入和在子宫内发育，并可能最终改变方法工程转基因小鼠。我们将使用这些新工具来确定精确的细胞和分子机制，胚泡与养母的子宫相互作用。我们的第二个挑战将是制造人造的基质，包括水凝胶和蜕膜细胞外基质的蛋白质，以促进植入事件同时，我们将为天然和合成胚胎设计合成胎盘样结构，使用来自滋养层和子宫内膜组织的类器官发育。这些系统将允许调查和跟踪如何损害植入前和围植入期的发展，如接触病原体，毒素或致畸剂影响随后的发展和生活。我们的第三个挑战是利用这些系统来发现伴随植入的分子事件。我们将利用我们的体外胎盘系统，以调查化学和物理信号事件的关键，发展，并确定如何改善胚胎外的贡献影响胚胎发育直到神经形成这些创新将使我们最终破译一个发展阶段，这是我们所不知道的，也是我们所不知道的。这将使我们深入了解一个时代的发展当大多数怀孕失败，从而导致辅助生殖技术的进步，它将提供新的筛选路线的药物测试和环境安全;它将促进我们的知识，干细胞在器官发生和再生医学中的应用。