FUNCTIONAL ANALYSIS OF ACTIVINS DURING DEVELOPMENT

在哺乳动物中，大约有10万个基因控制着 一个有机体的发展。 为了使开发正常进行， 一定是成千上万个基因协同作用 在任何给定的细胞的存在。从受精开始， 这些基因产物的精确表达在胚胎期是必需的， 胎儿、产后和成人发育。 甚至一个的异常合成 这些基因产物可能是灾难性的-出生缺陷，癌症， 不孕不育，甚至死亡都是可能的， 程序被修改了。 为了充分了解人类的这些过程， 是有必要的生理模型， 在创造人类的过程中发生的发展事件。 为此，我们选择小鼠作为我们的哺乳动物模型。 问题研究 现在有可能修改小鼠基因组， 带有精确基因突变的小鼠品系。 利用这项技术， 我们的实验室创造了几个有先天缺陷的模型。 为 例如，激活素β A和卵泡抑素基因突变的小鼠 在出生时死亡，并有腭裂，一种常见的人类出生缺陷， 病因不明。 此外，小鼠激活素受体的突变 II型基因有骨骼和面部畸形， 人类皮埃尔-罗宾综合征;患有该综合征的人类新生儿 下颌骨的缺陷，导致呼吸窘迫， 立即手术矫正。 在这份拨款申请中，我们将 利用这些先前创建的小鼠模型以及额外的 模型（即，缺乏激活素betaC和betaE的小鼠）来研究这一点 复杂的信号转导系统具体目标是：1）定义 肝脏特异性TGF-β超家族成员激活素的功能 2）进行激活素betaB“敲入”以尝试激活betaC和betaE; 拯救激活素β A敲除小鼠;和3）研究出生后 使用诱导型敲除的卵泡抑素和激活素β A的功能 系统. 使用这些小鼠作为体内哺乳动物模型的未来研究 系统将使我们能够更充分地了解相互关联的作用 这些蛋白质在哺乳动物发育和生理学中的作用。

In mammals, there are approximately 100,000 genes which govern the development of an organism. For development to proceed normally, there must be coordinate interaction of tens of thousands of these gene products in any given cell of the being. Beginning with fertilization, precise expression of these gene products is required during embryonic, fetal, postnatal, and adult development. Aberrant synthesis of even one of these gene products can be disastrous - birth defects, cancer, infertility, and even death are all possible when this developmental program is altered. To fully understand these processes in humans, it is necessary to have physiological models that closely mimic developmental events which occur during the creation of a human being. Toward this end, we have chosen the mouse as the mammalian model for our studies. It is now possible to modify the mouse genome to generate strains of mice with precise genetic mutations. Using this technology, our laboratory has created several models which have birth defects. For example, mice with mutations in the activin betaA and follistatin genes die at birth and have cleft palate, a common birth defect in humans of unknown etiology. In addition, mice a mutations in the activin receptor type II gene have skeletal and facial abnormalities which mimic the human Pierre-Robin syndrome; human newborns with this syndrome have defects in the mandible, leading to respiratory distress which must be surgically corrected immediately. In this grant proposal, we will utilize these previously created mouse models as well as additional models (i.e., mice lacking activins betaC an betaE) to study this complex signal transduction system. The Specific Aims are: 1) Define the functions of the liver-specific TGF-beta-superfamily members, activins betaC and betaE; 2) Perform an activin betaB "knockin" to attempt a rescue of activin betaA knockout mice; and 3) Study the postnatal functions of follistatin and activin betaA using inducible knockout systems. Future studies using these mice as in vivo mammalian model systems will enable us to more fully understand the interrelated roles of these proteins in mammalian development and physiology.