ACTIVIN REGULATION OF SMAD7 IN THE PITUITARY

激活素在垂体-性腺轴的调节中起着关键作用。这项拟议研究的长期目标是更好地了解激活素在调节脑垂体细胞生理学中的作用。短期目标是通过回答一些关于激活素信号转导机制的具体问题，为这种理解奠定基础。我们实验室的初步数据显示，Smad7在垂体前叶有表达。虽然Smad7显然是激活素信号的拮抗剂，但它在脑下垂体中的作用仍然很大程度上尚不清楚。我们假设Smad7是脑下垂体内的一个重要的调节因子，抑制激活素调节的脑下垂体细胞功能。在特定目标I中，研究将在体外检测Smad7在大鼠垂体前叶细胞中的产生和表达的调节。在特定目的II中，研究目的在于确定小鼠Smad7基因的结构以及激活素对其在促性腺激素细胞系中的调节作用。最后，在特定目标III下，我们建议研究Smad7在基础和激活素调节的促性腺激素细胞功能中的作用。本研究方案中概述的研究非常重要，因为确定激活素信号通路是更好地了解激活素的内分泌作用、各种内分泌疾病的发病机制以及开发治疗垂体功能障碍的工具的重要一步。

Activin plays a critical role in the regulation of the pituitary-gonadal axis. The long-term objectives of the proposed research are to better understand the role of activin in the regulation of pituitary cell physiology. The short-term goals are to establish the basis for this understanding by answering some specific questions concerning the mechanisms underlying activin signal transduction. Preliminary data from our laboratory demonstrates Smad7 expression in the anterior pituitary. While it is clear that Smad7 is an antagonist of activin signaling, its role in the pituitary remains largely unexplored. We hypothesize that Smad7 is an important modulatory factor within the pituitary, inhibiting activin-regulated pituitary cell function. In Specific Aim I, studies will examine the production and regulation of Smad7 expression in rat anterior pituitary cells, in vitro. In Specific Aim II, studies aim to characterize the structure of the mouse Smad7 gene and its regulation by activin in a gonadotrope cell line. Lastly, under Specific Aim III, we propose to examine the role of Smad7 on basal and activin-regulated gonadotrope cell function. The studies outlined in the present research proposal are important as defining the activin signaling pathway is a pivitol step toward better understanding the endocrine role of activin, the pathogenesis of various endocrine disorders, and the development of tools toward the treatment of pituitary dysfunction.