Beta-catenin biology in regeneration of uterine smooth muscle

β-连环蛋白生物学在子宫平滑肌再生中的作用

• 批准号: 7861147
• 负责人: JOSE M. TEIXEIRA
• 金额: $ 0.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7861147
• 关键词: Actins; Adherens Junction; Adhesions; Adipocytes; Adipose tissue; Adult; Benign; Biology; Bone Marrow; Bone Marrow Cells; Cadherins; Cell Nucleus; Cells; Characteristics; Complex; Cytoskeleton; Development; Duct (organ) structure; Dyes; Endometrial; Endometrium; Epithelium; Estrous Cycle; Etiology; Family; Fatty acid glycerol esters; Female Genital Neoplasms; Flow Cytometry; Gene Expression; Genes; Human; Hysterectomy; Knowledge; Lead; Leiomyoma; Link; Mediating; Medical; Mesenchyme; Molecular; Mus; Muscle; Muscle Cells; Myometrial; Natural regeneration; Nuclear; Operative Surgical Procedures; Pathology; Pathway interactions; Phenotype; Play; Pregnancy; Primary Cell Cultures; Process; Protein Isoforms; Reporting; Role; Signal Transduction; Skeletal Muscle; Skeletal Muscle Satellite Cells; Smooth Muscle; Smooth Muscle Myocytes; Source; Stem cells; Stress; Structure of paramesonephric duct; TCF Transcription Factor; Tissues; Tube; Uterine Fibroids; Uterus; Woman; adipocyte differentiation; base; beta catenin; member; myogenesis; myometrium; postnatal; precursor cell; progenitor; regenerative; repaired; residence; satellite cell; tumor; uterine smooth muscle cell

DESCRIPTION (provided by applicant): Although the uterus is indispensable for propagation, and thus survival, of mammalian species, its differentiation from the primordial Mullerian ducts is not well understood. We hypothesize that 2-catenin plays a major role in postnatal uterine development and that its dysregulated function may be an underlying cause of leiomyomata, the most common gynecologic tumor. Conventional Wnt- mediated signal transduction occurs by the stabilization of 2-catenin and its translocation to the nucleus and interaction with the transcription factors TCF/LEF to modulate target gene expression. Additionally, 2-catenin plays an essential role in linking adherens junctions with the actin cytoskeleton. We are investigating the function of 2-catenin in uterine development and have found that targeted deletion of 2-catenin in mouse uterus leads to progressive replacement of smooth muscle with fat in the myometrium with estrous cycling. These results suggested that there is a regenerative cell in the uterus that is dependent on 2-catenin function and is hormonally regulated. We propose to continue these studies by- (I) Identifying the uterine smooth muscle cells that behave like the regenerative satellite cells in skeletal muscle. (II) Determining the source of the cells that contribute to uterine smooth muscle. (III) Determining whether the muscle-fat phenotype is due to the adhesion or the nuclear function of 2-catenin. The results of these studies will provide a better understanding of postnatal uterine development and should provide clues to the etiology of uterine muscle pathologies such a leiomyomata, which are more commonly known as uterine fibroids. More knowledge is needed about the process of uterine development and function, particularly when these processes are perturbed as with uterine fibroids, a significant indicator for hysterectomy. Understanding the mechanisms governing development of these benign tumors in the uterus should lead to safe, long-term medical therapies based on scientific rationales that could benefit thousands of women annually who might be spared surgery.

描述（由申请人提供）：尽管子宫对于哺乳动物物种的传播不可或缺，因此其生存是必不可少的，但其与原始的穆勒风管的区分尚不清楚。我们假设2-catenin在产后子宫发育中起主要作用，并且其失调的功能可能是平瘤的根本原因，这是最常见的妇科肿瘤。常规WNT介导的信号转导通过2-catenin的稳定及其转移到核并与转录因子TCF/LEF相互作用来调节靶基因表达。另外，2-catenin在将粘附连接与肌动蛋白细胞骨架联系起来中起着至关重要的作用。我们正在研究2-catenin在子宫发育中的功能，并发现针对小鼠子宫中2-catenin的靶向缺失会导致逐步替代平滑肌在肌层中用发酵性循环进行脂肪。这些结果表明，子宫中有一个再生细胞取决于2-catenin功能，并且受荷尔蒙调节。我们建议通过 - （i）识别类似于骨骼肌中的再生卫星细胞的子宫平滑肌细胞来继续这些研究。 （ii）确定有助于子宫平滑肌的细胞来源。 （iii）确定肌肉脂肪表型是由于2-catenin的粘附或核功能引起的。这些研究的结果将更好地了解产后子宫发育，并应为子宫肌肉病理学的病因提供线索，例如平滑肌瘤，通常称为子宫肌瘤。 需要更多关于子宫发育和功能过程的知识，尤其是当这些过程与子宫肌瘤一样扰动时，这是子宫切除术的重要指标。了解有关子宫中这些良性肿瘤发展的机制，应基于科学原理的安全，长期的医疗疗法，每年可能受益于可能幸免于手术的女性。