Reproductive Endocrinology And Infertility Clinical Training Program

生殖内分泌与不孕不育临床培训项目

• 批准号: 8351272
• 负责人: James H. Segars
• 金额: $ 213.53万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8351272
• 关键词: AKAP13 gene; Alkylating Agents; Alleles; American; Animals; Apoptosis; Biological Markers; Biological Preservation; Cardiac; Cardiac Myocytes; Cell Communication; Cells; Characteristics; Chemotherapy-Oncologic Procedure; Childhood; Clinical; Clinical Research; Clinical Trials; Cyclophosphamide; Development; Disease; Estrogen Receptors; Estrogens; Exposure to; Extracellular Matrix; Fellowship Program; Fibroid Tumor; Frequencies; Functional disorder; Gene Targeting; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Infertility; Infertility study; Knock-out; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Mechanics; Methods; Migraine; Mus; National Institute of Child Health and Human Development; Neuraxis; Ovarian; Pain; Patients; Phenotype; Population; Prevalence; Primordial Follicle; Proteins; Receptor Activation; Reporting; Reproduction; Reproductive Endocrinology; Reproductive Health; Reproductive Medicine; Research; Research Personnel; Role; Signal Transduction; Societies; Stimulus; Superficial Lesion; System; Toxin; Training Programs; Ultrasonography; United States; Uterine Fibroids; Woman; Wood material; abstracting; analog; animal data; cancer therapy; chemotherapy; chronic pain; chronic pelvic pain; clinically relevant; cohort; endometriosis; girls; health disparity; healthy volunteer; immune function; improved; in utero; meetings; myocyte-specific enhancer-binding factor 2; offspring; patient population; programs; racial/ethnic difference; reproductive; reproductive function; response; rho; special interest group; symposium; tumor

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. In the past year we have found that cells that comprise a fibroid have impaired responses (decreased) to mechanical stimuli. Additionally, we completed a collaborative clinical trial led by Drs. Wood, Stratton and Venkatesan of MRI-guided high frequency ultrasound (HIFU) for the non-surgical treatment of uterine fibroids. In the coming year we plan to begin a second study with HIFU for the non-surgical treatment of uterine fibroids. Chronic Pelvic Pain and Endometriosis We have continued to investigate the association of chronic pelvic pain and endometriosis. This ongoing clinical study led by Dr. Stratton examines the relationship between chronic pelvic pain and endometriosis in three cohorts of women: women with chronic pain and endometriosis, those with chronic pelvic pain but no evidence of endometriosis, and healthy volunteers. Chronic pelvic pain is associated with endometriosis, but we have found that the location of superficial lesions does not correlate with pain location in a cohort of women with endometriosis. We also have found that two thirds of women with chronic pelvic pain have migraine headaches, a finding independent of endometriosis. These findings suggest that chronic pelvic pain associated with endometriosis is likely the result of central nervous system sensitization and myofascial dysfunction. Assessment and preservation of ovarian function in women and young girls undergoing cancer treatment Because of improved survival and effective chemotherapy for cancers, many young girls and women now are able to survive cancer, but find that reproductive function is impaired. In the past year we have completed animal and clinical investigations with plans to continue additional studies in a pediatric clinical populations and additional animal studies to examine potential mechanism(s) for preservation of primordial follicles after exposure to alkylating agents. We will also continue our study of diminished ovarian reserve in infertility patients. In the past year we reported animal data that suggested GnRH analogues preserve primordial follicles after exposure to the chemotherapy agent, cyclophosphamide. Results suggested that this may be due to a decrease in apoptosis (programmed cell death). In the coming year, we plan to investigate possible mechanism(s) involved. We also plan to begin a clinical study to examine new biomarkers of ovarian reserve in this patient population. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. Dr. Armstrong helped to established a Special Interest Group and national research network on the topic of Health Disparities. Investigators in the branch helped to arrange the a new abstract session at the Annual Meeting of the American Society of Reproductive Medicine on this reproductive health disparities. In the past year, Dr. Armstrong also led an NICHD-hosted conference on Health Disparities. In the coming year, the plans are to initiate a project to examine ethnic and racial differences in exposure to environmental reproductive toxins. 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 made progress on development of a conditional gene targeting strategy using the Cre-Lox system in mice. Plans are to examine the phenotypes of the conditionally-targeted offspring. In addition, in the coming year we will examine the phenotypes of mice heterozygous for the AKAP13 null allele to determine whether these mice may have subtle abnormalities in estrogen or glucocorticoid signaling.

子宫肌瘤 到生育年龄结束时，超过 50% 的美国女性会患上子宫肌瘤，使这种疾病成为女性最常见的生殖疾病。尽管这种情况很普遍，但人们对这种情况仍然知之甚少。子宫肌瘤的一个显着特征是肿瘤内的细胞产生紊乱且过多的细胞外基质（ECM）。之前，我们检查了 ECM 以及产生这种过度纤维化 ECM 的细胞的特征，并发现肌瘤内细胞的机械信号（一种细胞通讯和激活的方法）发生了改变。在过去的一年中，我们发现构成肌瘤的细胞对机械刺激的反应受损（下降）。此外，我们完成了由博士领导的合作临床试验。 Wood、Stratton 和 Venkatesan 提出了 MRI 引导的高频超声 (HIFU) 用于子宫肌瘤的非手术治疗。明年，我们计划开始第二项高强度聚焦超声非手术治疗子宫肌瘤的研究。 慢性盆腔疼痛和子宫内膜异位症 我们继续研究慢性盆腔疼痛和子宫内膜异位症的关联。这项由 Stratton 博士领导的正在进行的临床研究在三组女性中检查了慢性盆腔疼痛和子宫内膜异位症之间的关系：患有慢性疼痛和子宫内膜异位症的女性、患有慢性盆腔疼痛但没有子宫内膜异位症证据的女性以及健康志愿者。慢性盆腔疼痛与子宫内膜异位症相关，但我们发现，在子宫内膜异位症女性队列中，浅表病变的位置与疼痛位置无关。 我们还发现，三分之二患有慢性盆腔疼痛的女性患有偏头痛，这一发现与子宫内膜异位症无关。 这些发现表明，与子宫内膜异位症相关的慢性盆腔疼痛可能是中枢神经系统敏化和肌筋膜功能障碍的结果。 接受癌症治疗的妇女和年轻女孩卵巢功能的评估和保存 由于癌症生存率的提高和有效的化疗，许多年轻女孩和妇女现在能够在癌症中存活下来，但发现生殖功能受到损害。在过去的一年中，我们完成了动物和临床研究，并计划继续在儿科临床人群中进行更多研究，并进行更多动物研究，以检查暴露于烷化剂后保存原始卵泡的潜在机制。我们还将继续对不孕症患者卵巢储备功能下降的研究。去年，我们报道的动物数据表明，GnRH 类似物在接触化疗药物环磷酰胺后可以保护原始卵泡。 结果表明，这可能是由于细胞凋亡（程序性细胞死亡）减少所致。在来年，我们计划调查可能涉及的机制。我们还计划开始一项临床研究，以检查该患者群体中卵巢储备的新生物标志物。 不孕不育和生殖健康差异 我们单位继续对不孕不育和生殖健康差异进行研究。阿姆斯特朗博士帮助建立了一个关于健康差异主题的特别兴趣小组和国家研究网络。 该分会的研究人员帮助在美国生殖医学会年会上安排了一次关于生殖健康差异的新摘要会议。 去年，阿姆斯特朗博士还主持了 NICHD 主办的健康差异会议。来年，计划启动一个项目来检查种族和种族在接触环境生殖毒素方面的差异。 BRX（也称为 AKAP13）在心脏发育、免疫功能和生殖中的作用 我们之前对我们小组克隆的基因 BRX (AKAP13) 的研究表明，这种大的 Rho-GEF 原癌蛋白参与雌激素和糖皮质激素受体的激活。我们之前发现，BRX 基因产物通过小鼠心肌细胞发育过程中的重要转录程序协调 G-sub-alpha-s 和 Rho 信号传导，其中涉及肌细胞增强因子 2 C (MEF2C)。带有两个 AKAP13 基因缺陷拷贝（敲除）的小鼠在子宫内死亡。去年，我们在小鼠体内使用 Cre-Lox 系统开发条件基因靶向策略方面取得了进展。计划检查有条件靶向的后代的表型。此外，明年我们将检查 AKAP13 无效等位基因杂合小鼠的表型，以确定这些小鼠的雌激素或糖皮质激素信号传导是否可能存在细微异常。