Regulation of Mammary Gland Development by Sirtuin 4

项目摘要 线粒体酶sirtuin 4（SIRT 4）在乳腺癌组织中下调，但其原因是 不清楚为了阐明这一点，我们首先试图确定SIRT 4在正常乳腺组织中的作用。 我们已经发现SIRT 4对于确保正常的乳房发育至关重要。在完全缺乏 SIRT 4（SIRT 4KO小鼠）的乳腺在青春期不完全发育。因此，他们不生产 怀孕期间母乳不足，几乎100%的婴儿在出生后两天死亡。我们 现在试图揭示SIRT 4影响乳腺发育的机制。首先，我们寻求 探讨卵巢激素17β-雌二醇（E2）和孕酮（P4）在介导卵巢恶性肿瘤中的作用。 SIRT 4对乳腺发育的影响（目的1）。这两种激素对启动生长至关重要 在青春期和妊娠期的产乳乳腺导管和SIRT 4KO中观察到的乳腺缺陷 小鼠的E2或P4信号传导被破坏的缺陷。此外，由于SIRT 4是 在线粒体中发现，并已知有许多代谢作用，我们试图调查的可能性， SIRT 4通过控制乳腺中的营养代谢来调节乳腺发育（目的2）。改变 小鼠和人类的代谢状态都显示出抑制乳腺发育。比如说， 体重过轻和超重的小鼠都有乳房发育受损， 哺乳期因此，我们试图确定SIRT 4对营养代谢的已知作用是否可能有助于 SIRT 4如何调节乳腺发育。总的来说，我们提出的研究将揭示SIRT 4的新作用。 调节乳房发育。最终，通过研究SIRT 4如何影响正常乳腺癌， 从生理学上讲，我们可以更好地理解为什么SIRT 4表达水平在乳腺癌组织中下调 以及这是否会导致疾病进展。

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.