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决定因素之一。胎盘形成母亲和胎儿之间的机械和生理联系，支持生长和发育。如果它不能正常发育，可能会出现严重的问题，包括母亲和后代的死亡。胎盘是在胚胎的一部分，一组特殊的细胞“侵入”子宫壁，附着在胚胎上后发育的。这些细胞，称为滋养层，然后分裂产生多核结构，使母亲和胎儿之间的氧气和营养物质的转移。尽管胎盘的重要性，我们仍然有一个贫穷的理解，在其形成的关键早期阶段的细胞和分子事件。 我在胎盘生物学的研究计划侧重于滋养层生物学，理解的长期目标（1）独特的滋养层细胞群体在胎盘发育中的作用，包括影响滋养层行为的因素;和（2）参与滋养层成熟和功能的细胞和分子机制。这里提出的研究是实现这些目标的第一步。 在短期内，我的目标是表征分子ADAM 12的重要性，以及A去整合素和金属蛋白酶（ADAM）基因家族在滋养层细胞生物学中的相关成员。ADAM基因具有独特的特性，使它们能够影响许多发育途径中常见的过程。特别是，这些分子参与细胞粘附和运动。 拟议的研究将检验ADAM蛋白在滋养层功能和胎盘发育中发挥核心作用的假设。使用培养的滋养层细胞和来自收获胎盘的组织，我将使用先进的细胞和分子方法来确定ADAM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层生物学和胎盘形成所涉及的分子机制的理解。这项工作也将有助于对ADAM蛋白的新知识，关于其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.