Examining the importance of ADAM metalloproteinases in trophoblast biology

胎盘的正确形成是哺乳动物成功繁殖的最重要的决定因素之一。胎盘在母亲和胎儿之间形成机械和生理联系，支持生长和发育。如果发育不正常，可能会对母亲和后代造成严重的问题，包括死亡。胎盘是胚胎的一部分在一组特殊的细胞“侵入”子宫壁后发育出来的，这些细胞附着在胚胎上。这些细胞被称为滋养层细胞，然后分裂形成多核结构，使母亲和胎儿之间能够转移氧气和营养。尽管胎盘很重要，但我们对胎盘形成的关键早期阶段所涉及的细胞和分子事件仍然知之甚少。我在胎盘生物学方面的研究重点是滋养细胞生物学，其长期目标是了解(1)独特的滋养细胞群体在胎盘发育中的作用，包括影响滋养细胞行为的因素；(2)涉及滋养细胞成熟和功能的细胞和分子机制。这里提出的研究是迈向这些目标的第一步。短期内，我的目标是研究ADAM12分子和ADAM基因家族的相关成员在滋养层细胞生物学中的意义。ADAM基因具有独特的特征，使它们能够影响许多发育途径中常见的过程。特别是，这些分子参与了细胞的黏附和运动。拟议的研究将检验亚当蛋白在滋养层功能和胎盘发育中发挥核心作用的假设。利用培养的滋养层细胞和来自采集的胎盘的组织，我将使用先进的细胞和分子方法来确定亚当氏症如何影响滋养层细胞的行为和功能。这些研究将提高我们对滋养细胞生物学和胎盘形成的分子机制的理解。这项工作还将有助于对亚当蛋白的新知识，因为它在发育生物学和其他器官系统中的重要性。

Correct formation of the placenta is one of the most important determinants of successful reproduction in mammals. The placenta forms the mechanical and physiologic link between mother and fetus, supporting growth and development. If it does not develop properly, there can be serious problems, including death, for both mother and offspring. The placenta develops after a special group of cells that are part of the embryo ‘invade’ into the wall of the uterus, attaching the embryo. These cells, called the trophoblast, then divide to create multi-nuclear structures that enable transfer of oxygen and nutrients between mother and fetus. Despite the importance of the placenta, we still have a poor understanding of the cellular and molecular events involved in the critical early stages of its formation. My research program in placental biology focuses on trophoblast biology, with the long-term objectives of understanding (1) the role of unique trophoblast cell populations in placental development, including the factors affecting trophoblast behavior; and (2) the cellular and molecular mechanisms involved in trophoblast maturation and function. The research proposed here is the first step towards these objectives. In the short-term, my aim is to characterize the significance of the molecule ADAM12, and related members of the A Disintegrin and Metalloproteinase (ADAM) gene family in trophoblast cell biology. ADAM genes have unique characteristics that enable them to affect processes common in many developmental pathways. In particular, these molecules are involved in cell adhesion and movement. The proposed studies will test the hypothesis that ADAM proteins play a central role in trophoblast function and placenta development. Using cultured trophoblast cells and tissues derived from harvested placenta, I will use advanced cellular and molecular methods to determine how ADAM’s affect trophoblast cell behavior and function. These studies will improve our understanding of the molecular mechanisms involved in trophoblast biology and placental formation. This work will also contribute new knowledge about ADAM proteins, with respect to its importance in developmental biology and in other organ systems.