ROLE OF EGF/TGF ALPHA IN ADIPOSE TISSUE DEVELOPMENT

表皮生长因子（EGF）的抑制作用与转化 生长因子α（TGF-α）对早期脂肪组织发育的作用将 使用畸胎瘤衍生的成脂细胞系进行体外研究 1246和新生脂肪细胞前体的原代培养，以及通过 用EGF治疗新生动物和使用遗传性肥胖 小鼠品系。 我们已经证明EGF/TGF-α是有效的抑制剂， 脂肪分化的研究。 本 因此，我们建议研究EGF是否可以发挥作用。 重要的调节作用，在维持未分化的 在早期发育中脂肪细胞前体的阶段。 实验 建议1）确定EGF作用的细胞内途径， 脂肪分化; 2）研究TGF-α/EGF表达 在维持未分化阶段的脂肪细胞; 3）研究 EGF/TGF-α对体内脂肪组织发育的影响 正常和肥胖动物; 4）确定是否在水平上异常 EGF（TGF-α），在其受体水平和/或 在肥胖动物中发现了它们的信号传导途径。 为 进行这项工作，我们已经开发了一个体外模型系统， 由畸胎瘤衍生的成脂细胞系组成，该细胞系 在确定的培养基中分化，并对EGF和TGF-α，a - 产生TGF-α的分化缺陷细胞系1246-3A， 新生脂肪细胞前体的原代培养， EGF/TGF-α的作用。 而且我们 建立了一个体内动物模型系统， 研究体内脂肪组织发育。 对这一问题的研究 体外-体内模型系统沿着使用生物化学和 分子生物学技术适用于了解激素 控制早期脂肪组织发育。 这项研究很重要 因为：脂肪细胞的测定发生在胎儿和早期 出生后，早发性肥胖很快出现在人类 肥胖通常与内分泌失调有关， 表明脂肪组织的发育受激素的密切控制， 生长因子

The inhibitory effect of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) on early adipose tissue development will be investigated in vitro using the teratoma-derived adipogenic cell line 1246 and primary culture of newborn adipocyte precursors, and in vivo by treatment of newborn animals with EGF and by using genetically obese strains of mice. We have shown that EGF/TGF-alpha are potent inhibitors of adipose differentiation in vitro and in vivo. In the present application, we are proposing to investigate whether EGF could play an important regulatory role in the maintenance of the undifferentiated stage in adipocyte precursors in early development. Experiments are proposed 1) to determine the intracellular pathway of EGF action on adipose differentiation; 2) to investigate the TGF-alpha/EGF expression in the maintenance of undifferentiated stage in adipocytes ; 3) to study the effect of EGF/TGF-alpha on adipose tissue development in vivo in normal and obese animals; 4) to determine if abnormalities at the level of EGF (TGF-alpha) , at the level of their receptors and/or at the level of their signal transduction pathway are found in obese animals. For performing this work, we have developed an in vitro model system consisting of a teratoma-derived adipogenic cell line which differentiates in defined medium and responds to EGF and TGF-alpha, a differentiation-deficient cell line 1246-3A which produces TGF-alpha and primary culture of newborn adipocyte precursors which differentiate in defined medium and respond to EGF/TGF-alpha. Moreover, we have established an in vivo animal model system which is appropriate for investigating adipose tissue development in vivo. The study of this in vitro - in vivo model system along with the use of biochemical and molecular biology techniques is suitable for understanding the hormonal control of early adipose tissue development. This study is important since: the determination of adipocyte takes place during fetal and early post-natal life, early-onset obesity appears very quickly in human development, obesity is often associated with endocrine disorders thus suggesting a close control of adipose tissue development by hormones and growth factors.