Estrogen and Abdominal Muscle Fibrosis

雌激素与腹肌纤维化

• 批准号: 9763879
• 负责人: Serdar E. Bulun
• 金额: $ 60.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-16 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763879
• 关键词: Abdominal Muscles; Adjuvant; Affect; Aging; Appearance; Area; Aromatase; Aromatase Inhibitors; Atrophic; Bioinformatics; Biological; Biopsy; Brain; ChIP-seq; Combined Modality Therapy; Data; Development; Disease; Elderly man; Estradiol; Estradiol Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Etiology; Extracellular Matrix; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Fulvestrant; Genes; Genetic; Genomics; Hernia; Hernia of abdominal cavity; Human; Immunoblotting; Immunohistochemistry; Incidence; Infection; Inguinal Hernia; Intervention; Knock-out; Label; Lead; Length; Letrozole; Maps; Mediating; Messenger RNA; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Weakness; Muscular Atrophy; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Pain; Pathway Analysis; Pathway interactions; Patients; Pattern; Peripheral; Pharmacologic Substance; Phenotype; Physiological; Physiology; Population; Postoperative Pain; Prevalence; Preventive; Production; Proteins; Pyrazoles; RNA analysis; Recurrence; Refractory; Role; S100A4 gene; Signal Transduction; Skeletal Muscle; Steroids; Surgeon; Testis; Testosterone; Time; Tissues; Transgenic Organisms; United States National Institutes of Health; Wild Type Mouse; abdominal wall; clinically relevant; estrogen disruption; estrogenic; experimental study; genetic signature; genome-wide; high risk population; histone modification; human disease; male; men; morphometry; mortality; mouse model; new therapeutic target; novel; postnatal; prevent; quadriceps muscle; receptor expression; repaired; skeletal muscle wasting; transcriptome; transcriptome sequencing

Although more than 1 in 4 men can be expected to develop symptomatic inguinal hernia, its mechanism is currently unknown. A subset of hernias may develop due to muscle fibrosis and myofiber atrophy leading to lower abdominal wall weakness. The long-term objective of this application is to determine the role of estrogen action in the etiology of lower abdominal muscle tissue (LAMT) fibrosis and atrophy associated with a subset of inguinal hernias. Aromatase, which converts testosterone to estradiol, is expressed only in the brain and testes of male mice. However, in men, aromatase is expressed in many additional tissues (muscle, fat) to provide physiologically necessary local quantities of estrogen. We generated transgenic humanized aromatase (Aromhum) mouse lines, each containing a single copy of the full-length human aromatase gene including its regulatory region, to mimic human patterns of estrogen production. Aromhum mice express the aromatase gene in peripheral tissues including the fibroblast component of the skeletal muscle tissue. LAMT has been found to be more sensitive to estradiol than the upper abdominal or quadriceps muscles, because the stroma of LAMT contains strikingly larger amounts of estrogen receptor- (ER)-expressing fibroblasts. Locally increased concentrations of estradiol in LAMT was associated with LAMT fibrosis characterized by progressive replacement of atrophic myocytes (muscle fibers) with ER-rich fibroblasts and excessive extracellular matrix, resulting in formation of large inguinal hernias in >90% of Aromhum male mice by 24 weeks. However, there were no hernias observed in any of the wild-type (WT) littermates. Microarray expression analysis of LAMT at four weeks (before the appearance of hernias) showed activated profibrotic pathways in Aromhum vs. WT mice. We hypothesize that enhanced estrogen action caused by locally formed estradiol drives muscle fibrosis and myocyte atrophy, leading to the hernia phenotype affecting highly estrogen-sensitive portions of skeletal muscle tissue, which is LAMT in Aromhum mice. This resonates with the remarkable and parallel increases in inguinal hernia incidence and increased aromatase expression in skeletal muscle and fat in aging men. To ascertain the underlying mechanisms, we propose the following aims: 1. Determine whether treatment with an aromatase inhibitor, an estradiol antagonist, or a highly selective ERα antagonist prevents fibrosis, LAMT muscle atrophy, and hernia formation in Aromhum mice. The estradiol/ER-mediated genomic mechanisms responsible for disordered proliferation of fibroblasts and extracellular matrix formation will be determined using integrative analysis of RNA-seq and ER-ChIP-seq on LAMT and fibroblasts. 2. Determine whether the genetic disruption of ER selectively in skeletal muscle fibroblasts affects LAMT fibrosis and hernia formation in Aromhum mice. In parallel, we will assess tissue steroid levels, aromatase and ERexpression, and estrogen responsive genes in abdominal muscle biopsies of men with or without hernia. We anticipate that this novel proposal will identify new drug targets and likely lead to the discovery of preventive approaches for hernia in high-risk populations.

尽管可以期望超过四分之一的男性发展出症状性腹股沟疝，但其机制是 目前未知。由于肌肉纤维化和肌纤维萎缩，可能会出现疝气的一部分 下腹壁无力。该应用的长期目标是确定雌激素的作用 下腹部肌肉组织（LAMT）纤维化的病因和与一部分相关的萎缩 腹股沟疝。将睾丸激素转化为雌二醇的芳香酶仅在大脑中表达并睾丸 雄性老鼠。但是，在男性中，在许多其他组织（肌肉，脂肪）中表达芳香化酶以提供 生理上必要的局部雌激素量。我们产生了转基因人源化芳香酶 （AROMHUM）小鼠系，每条包含全长人芳香酶基因的单个副本，包括其 调节区域，以模仿雌激素产生的人类模式。香气小鼠表达芳香酶基因 在包括骨骼肌组织的成纤维细胞成分的外周组织中。已发现LAMT 比上腹部或股四头肌更敏感，因为LAMT的基质 含有大量的雌激素受体-（ERR）表达成纤维细胞。局部增加 LAMT中雌二醇的浓度与以进行性为特征的LAMT纤维化有关 用富含ER的成纤维细胞和过量的细胞外基质代替萎缩性肌细胞（肌肉纤维）， 导致在24周内在> 90％的香气雄性小鼠中形成大型腹股沟疝。但是，那里 在任何野生型（WT）窝窝中都没有观察到疝气。 LAMT的微阵列表达分析 四个星期（在出现HARNIAS之前）显示了Aromhum与WT小鼠的激活纤维化途径。 我们假设由局部形成的雌二醇引起的增强的雌激素作用驱动肌肉纤维化和 肌细胞萎缩，导致疝表型影响高度雌激素敏感的骨骼 肌肉组织，在香气小鼠中是LAMT。这与显着和平行的增加共鸣 腹股沟疝的发生率和骨骼肌中芳香化酶表达增加，而衰老的男性则脂肪。到 确定基本机制，我们提出以下目的：1。确定是否使用 芳香酶抑制剂，雌二醇拮抗剂或高度选择性ERα拮抗剂可防止纤维化，LAMT 肌肉萎缩和香气小鼠中的疝气形成。雌二醇/ER介导的基因组机制 负责使用成纤维细胞增殖和细胞外基质形成的无序 在LAMT和成纤维细胞上对RNA-SEQ和ERCHIP-SEQ的综合分析。 2。确定是否 骨骼肌成纤维细胞中ER的遗传破坏会影响LAMT纤维化和疝气形成 在香气小鼠中。同时，我们将评估组织立体水平，芳香酶和ER表达以及雌激素 有或没有疝气的男性腹部肌肉活检中的反应基因。我们期待这本小说 提案将确定新的药物靶标，并可能导致发现疝气的预防方法 High-risk populations.