Beta-catenin biology in regeneration of uterine smooth muscle

描述（由申请人提供）：尽管子宫对于哺乳动物物种的繁殖和生存是不可或缺的，但其与原始苗勒管的分化尚不清楚。我们推测2-连环蛋白在出生后子宫发育中起主要作用，其功能失调可能是最常见的妇科肿瘤平滑肌瘤的潜在原因。传统的Wnt介导的信号转导通过2-连环蛋白的稳定化及其易位到细胞核并与转录因子TCF/LEF相互作用以调节靶基因表达而发生。此外，2-连环蛋白在连接粘附连接与肌动蛋白细胞骨架中起重要作用。我们正在研究2-catenin在子宫发育中的功能，并发现在小鼠子宫中靶向缺失2-catenin会导致子宫肌层中的平滑肌逐渐被发情周期中的脂肪取代。这些结果表明，在子宫中存在一种再生细胞，其依赖于2-连环蛋白的功能并受到子宫调节。我们建议继续这些研究-（一）确定子宫平滑肌细胞的行为像骨骼肌再生卫星细胞。(II)确定子宫平滑肌细胞的来源。(III)确定肌肉-脂肪表型是否是由于2-连环蛋白的粘附或核功能。这些研究的结果将提供一个更好的了解产后子宫发育，并应提供线索的子宫肌肉病变，如平滑肌瘤，这是更常见的称为子宫肌瘤的病因。 需要更多关于子宫发育和功能过程的知识，特别是当这些过程受到干扰时，如子宫肌瘤，子宫切除术的重要指标。了解子宫内这些良性肿瘤的发展机制，应该会导致基于科学原理的安全，长期的医学治疗，每年可以使成千上万的女性受益，这些女性可能会免于手术。

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.