MOLECULAR BASIS OF ADIPOGENESIS

描述：（改编自申请人摘要）在拟定研究中， 申请人的目标将是鉴定和表征哺乳动物基因 参与调节脂肪细胞分化的早期阶段。 目前，没有形态学或分子标记来识别 哺乳动物的脂肪细胞前体。这种分子开关 这些细胞的脂肪形成程序还没有被很好地理解。因此 申请人将集中于与可比较的生物学行为有关的分子。 在果蝇，黑腹果蝇，过程中，并测试是否 这些基因的同源物在哺乳动物系统中发挥类似的作用。水果 苍蝇携带一种叫做脂肪体的结构， 哺乳动物脂肪组织和肝脏的同源物。早期的研究 确定了在前体细胞形成中起关键作用的基因， 果蝇脂肪体的结构。一个这样的基因是果蝇蛇（srp）基因。 Serpent是一个有趣的基因，因为它是加塔家族的成员， 已被证明是果蝇发育的重要因素 脂肪体和造血系统。蛇也需要内胚层 肠道的发育、分化和形态发生。申请人 假设蛇的哺乳动物同源物，加塔家族， 转录因子，也表达在哺乳动物脂肪组织和发挥作用， 在脂肪形成中的重要作用。申请人的初步实验 证明至少有两个成员的加塔家族的转录 加塔-2和加塔-3因子在成人脂肪组织中高度表达 小鼠有趣的是，加塔-3表达仅限于白色而非棕色 脂肪组织此外，在分离的成熟细胞中未检测到表达。 提示脂肪细胞中加塔-3表达的主要来源 组织是脂肪细胞前体。这些因素有力地支持了这一点， 也在培养的3T3-F442A和3T3-L1前脂肪细胞中表达，但它们的 表达在分化过程中非常早地减少。表达时 它们组成性地阻断脂肪细胞的分化。 具体目标是（a）表征加塔的表达和生物学 B）研究加塔因子调节的机制 通过关注与脂肪细胞的潜在串扰来分化脂肪细胞， 成脂转录因子，和c）产生功能获得的转基因 小鼠以测试加塔对体内脂肪形成的生物学。通过这条线， 调查，申请人希望获得新的和重要的信息， 一个涉及脂肪生成的关键生物学过程。

DESCRIPTION: (Adapted from the applicant's abstract) In the proposed studies, the applicant's goal will be to identify and characterize mammalian genes involved in the regulation of early stages of adipocyte differentiation. Currently, there are no morphological or molecular markers to identify adipocyte precursors in mammals. The molecular switches that permit the adipogenic programming of these cells are not well understood. Therefore, the applicant will focus on molecules that have been implicated in comparable processes in the fruit fly, Drosophila Melanogaster, and test whether homologues of these genes play similar roles in mammalian systems. The fruit fly carries a structure called fat body that appears to be the functional homologue of mammalian adipose tissue and liver. Earlier studies have identified genes that play a crucial role in the formation of precursor cells of the Drosophila fat body. One such gene is the Drosophila serpent (srp) gene. Serpent is an interesting gene since it is a member of the GATA family and has been demonstrated to be an essential factor for the development of Drosophila fat body and the hemapoietic system. Serpent is also required for endodermal development and differentiation and morphogenesis of the gut. The applicant hypothesizes that the mammalian homologue(s) of serpent, GATA family of transcription factors, is also expressed in mammalian adipose tissue and plays an important role in adipogenesis. The applicant's preliminary experiments have demonstrated that at least two members of the GATA family of transcription factors, GATA-2 and GATA-3, are expressed highly in the adipose tissue of adult mice. Interestingly, GATA-3 expression is restricted to white and not brown adipose tissue. Furthermore, expression was not detected in isolated mature adipocytes suggesting that the primary source of GATA-3 expression in adipose tissue is adipocyte precursors. In strong support of this, these factors are also expressed in cultured 3T3-F442A and 3T3-L1 preadipocytes but their expression is diminished very early during differentiation. When expressed constitutively, they block the differentiation of adipocytes. Specific aims are to (a) characterize the expression and biology of GATA factors in adipocytes, b) study the mechanisms by which GATA factors regulate differentiation of adipocytes by focusing on potential crosstalk with adipogenic transcription factors, and c) generate gain of function transgenic mice to test the biology of GATA on adipogenesis in vivo. Through this line of investigation, the applicant hopes to obtain novel and important information on a key biological process involving adipogenesis.