Regulation of Mammary Gland Development by Sirtuin 4

项目摘要 线粒体酶sirtuin 4(SIRT4)在乳腺癌组织中下调，但原因是 不清楚。为了阐明这一点，我们首先试图确定SIRT4在正常乳腺组织中的作用。 我们发现SIRT4对于保证乳腺的正常发育是至关重要的。在小鼠中完全缺乏 在SIRT4(SIRT4KO小鼠)中，乳腺在青春期不完全发育。因此，它们不会生产 怀孕期间有足够的母乳，几乎100%的婴儿在出生后两天就会死亡。我们 现在试图揭示SIRT4影响乳腺发育的机制。首先，我们寻求 探讨卵巢激素17-β-雌二醇(E_2)和孕酮(P_4)在体内的调节作用 SIRT4对乳腺发育的影响(目标1)。这两种激素是启动生长所必需的。 青春期和妊娠期产奶乳腺导管与SIRT4KO中的乳房缺陷 小鼠让人想起E2或P4信号受阻的小鼠身上的缺陷。此外，由于SIRT4是 发现在线粒体中，并已知有许多代谢影响，我们试图调查的可能性 SIRT4通过控制乳腺中的营养代谢来调节乳腺发育(目标2)。更改后的 老鼠和人类的代谢状态都被证明会抑制乳房的发育。例如, 体重不足和超重的小鼠都有乳房发育受损，这可能导致乳房发育不足 哺乳。因此，我们试图确定SIRT4对营养代谢的已知影响是否可能有助于 SIRT4如何调控乳腺发育。总体而言，我们建议的研究将揭示SIRT4的新角色 在调节乳房发育方面。最终，通过研究SIRT4如何影响正常乳腺 生理学方面，我们可能更好地理解为什么乳腺癌组织中SIRT4的表达水平下调 以及这是否有助于疾病的进展。

Project Summary The mitochondrial enzyme sirtuin 4 (SIRT4) is downregulated in breast cancer tissue, but the reason for this is not clear. In order to elucidate this, we first sought to determine the role of SIRT4 in normal mammary tissue. We have discovered that SIRT4 is critical for ensuring normal mammary development. In mice with a total lack of SIRT4 (SIRT4KO mice), mammary glands do not fully develop during puberty. As a result, they do not produce enough maternal breast milk during pregnancy and nearly 100% of their young perish two days after birth. We now seek to uncover the mechanism by which SIRT4 influences mammary gland development. First, we seek to investigate the potential role of the ovarian hormones 17β-estradiol (E2) and progesterone (P4) in mediating the effects of SIRT4 on mammary development (Aim 1). These two hormones are essential for initiating growth of milk-producing mammary ducts during puberty and pregnancy and the mammary defects seen in SIRT4KO mice are reminiscent of the defects seen in mice with disrupted E2 or P4 signaling. Furthermore, since SIRT4 is found in mitochondria and is known to have many metabolic effects, we seek to investigate the possibility that SIRT4 regulates mammary development by controlling nutrient metabolism in mammary glands (Aim 2). Altered metabolic states in both mice and humans have been shown to inhibit mammary development. For example, both underweight and overweight mice have impaired mammary development that can result in insufficient lactation. Thus, we seek to determine whether the known effects of SIRT4 on nutrient metabolism may contribute to how SIRT4 regulates mammary development. Overall, our proposed studies will reveal a new role for SIRT4 in regulating mammary development. Ultimately, by investigating how SIRT4 influences normal mammary physiology, we may better understand why SIRT4 expression levels are downregulated in breast cancer tissue and whether this contributes to disease progression.