Post-translational regulation of aromatase in aging

衰老过程中芳香酶的翻译后调控

• 批准号: 10976001
• 负责人: Kevin Pruitt
• 金额: $ 6.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10976001
• 关键词: Post; translational; regulation; aromatase; aging

Summary: Alterations in estrogen signaling contribute to a spectrum of abnormalities ranging from skeletal dysplasias to Alzheimer’s disease (AD) that impact both physiology and behavior. The CYP19A1 gene encodes aromatase which is the final enzyme in the estrogen biosynthesis pathway that converts androgens to estrogens. Synthesis of estrogen throughout the body can be regulated spatially and temporally depending on the tissue. The impact of estrogen extends beyond stimulation of ER and ER and has recently been shown to regulate the function of G- protein coupled estrogen receptors in diverse tissues. Moreover, the impact of 17-estradiol (E2) on stromal and immune cells is important in the regulation of the immune system and dysfunctional signaling has been linked with auto-immune diseases. Despite the critically important role of aromatase in biology in tissues and organs ranging from the epithelial tissue to the brain to bones, many major knowledge gaps remain regarding the regulation of aromatase at the transcriptional and post-translational level. Recently, our lab made two major discoveries. First, our recent reports were the first to establish that Dishevelled proteins, key regulators of Wnt signaling, bind to multiple CYP19A1 tissue specific promoters and modulate aromatase expression. These recent observations could provide significant insight into mechanisms of aging-related pathologies. Recent reports establish links between CYP19A1 gene alterations and AD and show altered neuroendocrinology and steroidogenesis in women with AD. Animal models further show the importance of aromatase dysregulation in aging related pathologies. Second, our group was the first to identify novel post-translational modification (PTM) regulatory lysines that control aromatase enzyme activity. Prior to our report, nothing was known about the extent to which lysine acetylation modulates aromatase activity. We hypothesize that aromatase PTMs will be influenced by aging in vivo. We now demonstrate that aromatase PTMs modulate aromatase inhibitor sensitivity and proposed studies are significant because they will be the first to dissect newly identified post-translational mechanisms of aromatase control as a function of aging in mammary gland tissue as a function of age using different transgenic mouse models. We will also identify novel aromatase PTMs in mammary gland tissue as a function of age via LC- MS/MS acetylation mapping. These studies represent an exciting new angle since virtually nothing is known about the role of aromatase PTMs in vivo in mammary gland tissue in general, and in particular, as a function of age. We further hypothesize that there are novel aromatase PTMs that are characteristic of the age-linked mammary gland microenvironments.

摘要：雌激素信号的改变导致一系列异常， 从骨骼发育不良到阿尔茨海默病（AD），这些疾病会影响生理和行为。 CYP 19 A1基因编码芳香化酶，芳香化酶是雌激素生物合成的最终酶 将雄激素转化为雌激素的途径。全身合成雌激素可以 根据组织在空间和时间上进行调节。雌激素的影响 除了刺激ER β和ER β外，最近还显示可调节G- 蛋白偶联雌激素受体在不同的组织。此外，17 β-雌二醇（E2） 在免疫系统的调节中是重要的， 功能失调的信号传导与自身免疫疾病有关。尽管批评 芳香化酶在生物学中的重要作用， 大脑到骨骼，许多主要的知识差距仍然关于芳香化酶的调节， 转录和翻译后水平。最近，我们的实验室有两个重大发现。 首先，我们最近的报道首次证实了Wnt的关键调节因子Dishevelled蛋白， 信号传导，结合多种CYP 19 A1组织特异性启动子并调节芳香化酶 表情这些最新的观察结果可以提供重要的洞察机制 衰老相关的病理学。最近的报道建立了CYP 19 A1基因改变与 AD和显示改变的神经内分泌和类固醇生成的妇女与AD。动物模型 进一步显示了芳香酶失调在衰老相关病理中的重要性。第二、 我们的研究小组是第一个发现新的翻译后修饰（PTM）调节赖氨酸的人。 控制芳香化酶活性。在我们的报告之前，我们不知道 赖氨酸乙酰化调节芳香酶活性。我们假设芳香化酶PTMs 会受到体内老化的影响。我们现在证明芳香化酶PTM调节 芳香酶抑制剂敏感性和拟议的研究是重要的，因为它们将是第一个 剖析新发现的芳香化酶控制的翻译后机制， 使用不同的转基因小鼠模型作为年龄的函数的乳腺组织衰老。我们 还将通过LC鉴定乳腺组织中作为年龄函数的新型芳香酶PTM， MS/MS乙酰化图谱。这些研究代表了一个令人兴奋的新角度， 关于芳香酶PTM在乳腺组织中的体内作用通常是未知的， 特别是作为年龄的函数。我们进一步假设，有新的芳香化酶 PTM是与年龄相关的乳腺微环境的特征。