Regulation of Mammary Gland Development by Sirtuin 4

Sirtuin 4 对乳腺发育的调节

• 批准号: 10377410
• 负责人: FRANK KHAN HUYNH
• 金额: $ 14.65万
• 依托单位: SAN JOSE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377410
• 关键词: Affect; Age; Alveolus; Amino Acids; Birth; Breast Cancer Patient; Breast Epithelial Cells; Cell Line; Cell Transplantation; Data; Defect; Development; Disease Progression; Dose; Duct (organ) structure; Endocrine; Ensure; Environment; Enzymes; Estradiol; Estrogen Receptors; Estrous Cycle; Genes; Genotype; Genus Hippocampus; Growth; Histologic; Hormones; Human; Human Milk; Impairment; Knockout Mice; Lactation; Lipids; Mammary Duct; Mammary gland; Measures; Mediating; Metabolic; Metabolic hormone; Metabolism; Mitochondria; Mitochondrial Proteins; Mothers; Mus; Nutrient; Ovarian hormone; Overweight; Pathway interactions; Phenotype; Physiology; Play; Positioning Attribute; Pregnancy; Progesterone; Progesterone Receptors; Prognosis; Puberty; Radiolabeled; Regulation; Role; Signal Pathway; Signal Transduction; Sirtuins; Stomach; Stromal Cells; Tissues; Transplantation; Trees; Underweight; cell growth; complement C2a; falls; glucose metabolism; hormonal signals; malignant breast neoplasm; mammary; mammary gland development; metabolomics; milk production; nutrient metabolism; paracrine; postnatal; pup; response; therapeutic target

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.

项目摘要 线粒体酶Sirtuin 4（SIRT4）在乳腺癌组织中被下调，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对于确保正常的乳腺发育至关重要。在完全缺乏的小鼠中 在SIRT4（SIRT4KO小鼠）中，青春期期间乳腺并未完全发育。结果，它们不产生 怀孕期间有足够的遗物母乳，几乎是出生后两天的年轻灭亡。我们 现在试图发现SIRT4影响乳腺发育的机制。首先，我们寻求 研究卵巢激素17β-雌二醇（E2）和孕酮（P4）的潜在作用 SIRT4对乳腺发展的影响（AIM 1）。这两个恐怖对于启动增长至关重要 在青春期和怀孕期间产生奶牛的乳腺导管以及Sirt4ko中看到的乳腺缺陷 使小鼠想起了E2或P4信号中断的小鼠中看到的缺陷。此外，由于Sirt4是 在线粒体中发现，众所周知具有许多代谢作用，我们试图调查可能性 SIRT4通过控制乳腺中的营养代谢来调节乳腺发育（AIM 2）。改变 小鼠和人类的代谢状态均已证明抑制乳腺发育。例如， 体重不足和超重小鼠都损害了乳房发育，这可能导致不足 哺乳。这是，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如何调节乳腺发展。总体而言，我们提出的研究将揭示SIRT4的新作用 控制乳腺发展。最终，通过研究SIRT4如何影响正常乳腺 生理学，我们可以更好地理解为什么SIRT4表达水平在乳腺癌组织中下调 这是否有助于疾病进展。