Post-translational regulation of aromatase in aging

衰老过程中芳香酶的翻译后调控

• 批准号: 10572625
• 负责人: Kevin Pruitt
• 金额: $ 1.14万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 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 2023-10-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572625
• 关键词: 3-Dimensional; Acetylation; Age; Aging; Alzheimer' s Disease; Amino Acid Substitution; Anabolism; Androgens; Animal Model; Aromatase; Aromatase Inhibitors; Autoimmune Diseases; Autoimmunity; Automobile Driving; Basic Science; Behavior; Binding; Biology; Brain; Cell Proliferation; Cells; Characteristics; Chronic; Clinic; Data; Deacetylation; Development; Dsh protein; Enzymes; Epithelium; Estradiol; Estrogens; Foundations; Functional disorder; Future; GPER gene; Gene Mutation; Genetic Transcription; Growth; Immune; Immune system; Knowledge; Letrozole; Link; Lysine; Mammary Gland Parenchyma; Mammary gland; Maps; Mouse Mammary Tumor Virus; Neuroendocrinology; Organ; Pathologic; Pathology; Pathway interactions; Pattern; Physiology; Post-Translational Protein Processing; Post-Translational Regulation; Principal Investigator; Production; Protein Family; Proteins; RAS genes; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Steroid biosynthesis; Testing; Tissues; Transgenic Animals; Transgenic Mice; WNT Signaling Pathway; Woman; anastrozole; bone; cell motility; enzyme activity; immunoregulation; in vivo; inhibitor therapy; insight; mouse model; neoplastic; novel; polyoma middle tumor antigen; promoter; skeletal dysplasia; steroid hormone; translational barrier; virtual

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：雌激素信号的改变有助于异常范围 从骨骼发育不良到影响生理和行为的阿尔茨海默氏病（AD）。 CYP19A1基因编码芳香酶，这是雌激素生物合成中的最终酶 将雄激素转换为雌激素的途径。整个体内雌激素的合成可以 经常根据组织进行调节。雌激素的影响延伸 除了对ER和ER的模拟外，最近已被证明可以调节G-的功能 蛋白质偶联的潜水组织中的雌激素受体。此外，17-雌二醇（E2）的影响 在基质和免疫细胞上对免疫系统的调节很重要， 功能失调的信号传导与自动免疫性疾病有关。尽管有批判性 芳香酶在生物学中的重要作用在组织和器官中的重要作用，从上皮组织到 大脑到骨骼，关于芳香化酶调节的许多主要知识差距仍然存在 转录和翻译后水平。最近，我们的实验室发现了两个主要发现。 首先，我们最近的报告是第一个确定散乱的蛋白质，Wnt的关键调节剂 信号传导，与多个CYP19A1组织特异性启动子结合并调节芳香酶 表达。这些最近的观察结果可以提供对机制的重大见解 与衰老有关的病理。最近的报告建立了CYP19A1基因改变与 AD并显示AD女性的神经内分泌学和类固醇生成发生了改变。动物模型 进一步显示了芳香酶失调在相关病理学中的重要性。第二， 我们的小组是第一个识别新型翻译后修饰（PTM）调节赖氨酸的人 该控制芳香化酶活性。在我们的报告之前，对程度一无所知 赖氨酸乙酰化对此调节芳香化酶活性。我们假设芳香酶PTM 将受到体内衰老的影响。我们现在证明了芳香族PTMS调制 芳香酶抑制剂敏感性和提出的研究很重要，因为它们将是第一个 剖析芳香酶控制的新鉴定的后翻译后机制 使用不同的转基因小鼠模型，乳腺组织的衰老与年龄的关系。我们 还将通过LC-鉴定乳腺组织中新型的芳香酶PTM作为年龄的函数 MS/MS乙酰化映射。这些研究实际上是一个令人兴奋的新角度 一般而言 特别是作为年龄的函数。我们进一步假设有新的芳香酶 PTM是年龄相关的乳腺微环境的特征。