Reproductive Endocrinology And Infertility Clinical Training Program

子宫肌瘤 在美国，超过50%的女性在生育年龄结束时会患上子宫肌瘤，这使这种疾病成为女性中最常见的生殖障碍。尽管这种情况很普遍，但人们对这种情况仍然知之甚少。子宫肌瘤的一个显著特征是肿瘤内的细胞产生无序和过度的细胞外基质(ECM)。以前，我们已经检查了细胞外基质和产生这种过度和纤维化的细胞外基质的细胞特征，并发现在肌瘤内的细胞中，机械信号(一种细胞沟通和激活的方法)发生了变化。我们目前的研究集中在如何利用机械信号的这种改变状态来开发肌瘤的非手术治疗。 BRX(又称AKAP13)在心脏发育、免疫功能和生殖中的作用 我们以前对本课题组克隆的BRX(AKAP13)基因的研究表明，这个大的Rho-egf原癌蛋白参与了雌激素和糖皮质激素受体的激活。我们先前发现，BRX基因产物在小鼠心肌细胞发育过程中协调G-亚α-S和Rho信号与一个必要的转录程序，涉及心肌细胞增强因子2C(MEF2C)。带有两个AKAP13基因缺陷拷贝(敲除)的小鼠在子宫中死亡。在过去的一年里，我们在小鼠身上开发了一种使用Cre-Lox系统的条件性基因靶向策略，并检查了条件靶向后代的表型。我们发现，条件性基因敲除的小鼠直到Cre激活时才表现出心功能障碍，之后小鼠出现心输出量减少和扩张型心肌病的功能特征。 在接下来的一年里，我们将继续研究AKAP13在心脏病体内模型中的作用。此外，我们将使用Cre-Lox策略和特定于生殖道的Cre重组酶激活策略来扩展我们对AKAP13在生殖组织中作用的分析。

Uterine leiomyoma By the end of their reproductive years, over 50% of women in the United States develop uterine fibroids, making the condition the most prevalent reproductive disorder of women. Despite their prevalence, the condition remains poorly understood. One prominent feature of uterine fibroids is that cells within the tumors produce a disordered and excessive extracellular matrix (ECM). Previously, we have examined the ECM and characteristics of the cells that produce this excessive and fibrotic ECM and have found that mechanical signaling (a method of cell communication and activation) was altered in cells within a fibroid. Our current research focuses on how this altered state of mechanical signaling might be utilized to develop non-surgical treatments for fibroids. Role of BRX (also known as AKAP13) in cardiac development, immune function and reproduction Our previous studies of the gene BRX (AKAP13), cloned by our group, indicated that this large Rho-GEF protooncoprotein was involved in estrogen and glucocorticoid receptor activation. We previously found that the BRX gene product coordinates G-sub-alpha-s and Rho signaling with an essential transcription program in developing cardiomyocytes in mice, involving myocyte enhancer factor 2 C (MEF2C). Mice with two defective copies of the AKAP13 gene (knockout) died in utero. In the past year we have developed a conditional gene targeting strategy using the Cre-Lox system in mice and examined phenotypes of the conditionally-targeted offspring. We found that mice with the conditional knockout did not exhibit cardiac dysfunction until Cre activation occurred, after which the mice developed reduced cardiac output and functional features suggestive of dilated cardiomyopathy. In the coming year we will continue to examine the role of AKAP13 in this in vivo model of cardiac disease. Further, we will expand our analysis of the role of AKAP13 in reproductive tissues using the Cre-Lox strategy with reproductive-tract-specific strategies for activation of Cre recombinase.