Beta-catenin biology in regeneration of uterine smooth muscle

描述(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，但它与原始的米勒管的区别还不是很清楚。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--子宫肌瘤的潜在原因。传统的Wnt介导的信号转导是通过稳定2-catenin并将其移位到细胞核，并与转录因子Tcf/Lef相互作用来调节靶基因的表达。此外，2-连环蛋白在连接粘着连接和肌动蛋白细胞骨架方面起着至关重要的作用。我们正在研究2-连环蛋白在子宫发育中的作用，并发现在小鼠子宫中靶向缺失2-连环蛋白会导致动情周期中子宫肌层中的平滑肌逐渐被脂肪取代。这些结果表明，子宫中存在一种依赖2-连环蛋白功能并受激素调节的再生细胞。我们建议通过以下方式继续这些研究：(I)鉴定子宫平滑肌细胞，这些细胞的行为类似于骨骼肌中再生的卫星细胞。(2)确定子宫平滑肌细胞的来源。(Iii)确定肌肉-脂肪表型是由于2-连环蛋白的粘附性还是核功能。这些研究的结果将提供对出生后子宫发育的更好的了解，并应该为子宫肌肉病变的病因学提供线索，如子宫肌瘤，通常被称为子宫肌瘤。 需要更多地了解子宫发育和功能的过程，特别是当这些过程受到子宫肌瘤的干扰时，子宫肌瘤是子宫切除术的一个重要指标。了解这些子宫良性肿瘤的发展机制应该会导致基于科学原理的安全、长期的医疗疗法，这些疗法每年可以使成千上万的妇女受益，她们可能不必接受手术。

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.