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: 7968644
• 负责人: James H. Segars
• 金额: $ 139.49万
• 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/7968644
• 关键词: AKAP13 gene; Affect; African American; Age; Agonist; Apoptosis; Asians; Assisted Reproductive Technology; Biological Preservation; Cancer Survivor; Cardiac; Caring; Case Series; Cells; Characteristics; Child; Clinical; Clinical Research; Collaborations; Color; Cytoskeleton; Development; Disease; Excision; Fellowship Program; Fibroid Tumor; Frequencies; Functional disorder; Gonadotropin Releasing Hormone Inhibitor; Growth and Development function; Impairment; Infertility; Infertility study; Inflammation; Investigation; Leiomyoma; Lesion; Life; Link; Live Birth; Lymphocyte; Malignant Neoplasms; Mechanical Stress; Mechanics; Medical; Modality; Modeling; Mus; Nuclear; Ovarian; Ovarian Hyperstimulation Syndrome; Ovary; Pain; Patients; Pelvic Pain; Phenotype; Proteins; Proto-Oncogenes; Radiation; Raloxifene; Recurrence; Reproductive Endocrinology; Reproductive Health; Research; Research Personnel; Risk Factors; Role; Severity of illness; Signal Transduction; Spleen; Stress; Testing; Training Programs; Transforming Growth Factor beta; Ultrasonography; United States National Institutes of Health; Uterine Fibroids; Uterine myomectomy; Woman; Wood material; Work; activating transcription factor 3; age effect; age related; assisted reproduction; cancer therapy; chemotherapy; chronic pelvic pain; clinically relevant; cost; endometriosis; evidence base; expectation; girls; health disparity; hypothalamic-pituitary-adrenal axis; meetings; prevent; reproductive; reproductive function; response; versican

Uterine leiomyoma Uterine fibroids are a highly prevalent disease, but the fundamental causes of leiomyoma growth and development remain poorly understood. Our past studies have suggested that the altered extra cellular matrix (ECM) in fibroids might affect fibroid growth and development. In the past year, we found dysregulated expression of ATF-3 was a possible link between mechanical stress and fibroid development. In another study, we found that elevated levels of TGF-beta in fibroids led to increased expression of the ECM protein versican. Also during the past year, in a collaborative effort with the Drs. Wood and Venkatesan, the unit began a trial of MRI-guided high frequency ultrasound (HIFU) treatment for fibroids. In addition, we completed analysis of a case series examining the possible impairment of ovarian function by myomectomy (removal of fibroids). In the coming year, we plan to dissect the altered mechanical signaling in fibroids in greater detail and we also plan to expand studies of HIFU as a treatment modality for uterine fibroids. Endometriosis and Chronic Pelvic Pain In the past year in collaboration with Dr. Nieman, Dr. Stratton concluded a study of raloxifene for treatment of endometriosis-related pelvic pain. Contrary to expectations, raloxifene appeared to hasten, not prevent, the recurrence of pelvic pain. In collaboration with Drs. Greene and Sinaii, the group led by Dr. Stratton also examined the relationship between disease severity and patient characteristics from 1000 women with endometriosis. Using this approach the group devised a model of the characteristics of endometriosis lesions that were associated with pain. In the coming year, the group will conclude a clinical study of the hypothalamic pituitary-adrenal-axis in women with chronic pelvic pain and endometriosis. Assessment and preservation of ovarian function in women and girls undergoing cancer treatment Many young girls and women are cancer survivors but find that their reproductive function is irreparably damaged by chemotherapy or radiation. In the past year, the unit tested a murine model of medical treatment prior to chemotherapy. The model confirmed efficacy of pre-treatment with GnRH-therapy, which appeared to act by reducing apoptosis in ovaries of pre-treated mice. In the coming year we plan to investigate the mechanism by which GnRH-antagonist functions in the murine model and launch a clinical study of GnRH-agonist treatment prior to chemotherapy in young women. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. In the past year Dr. Armstrong was an investigator in a study that examined reproductive health disparities in 130,000 assisted reproduction cycles (ART). The study supported our prior work and revealed that the likelihood of live birth was reduced in women of African-American and Asian women. The reasons for this disparity remain unclear. To encourage research on reproductive health disparities, Dr. Armstrong chaired a meeting at NIH on Reproductive Problems in Women of Color in July 2009. The meeting spawned new studies and collaborations. During the past year, we also continued clinical studies of infertility related to evidence-based and cost-effective infertility care. We modeled the effect of age and FSH levels on cost of a live-born child at assisted reproduction. In another study we examined the difference between age-related increases in FSH and increases in FSH prior to age 35. In the coming year, we plan to examine the pathophysiology underlying ovarian hyperstimulation syndrome (OHSS), a major risk factor for women pursuing assisted reproductive technologies. Role of BRX (also known as AKAP13) in cardiac development We have continued our study of the protooncogene, BRX, cloned by our group (also known as AKAP13) and the study of the murine model of targeted deletion of the BRX gene. In collaboration with Dr. Kino, studies in the past year focused on the reduced size of the spleen in haplo-insufficient mice. Investigation of the phenotype led to the discovery that BRX was involved in the response of lymphocytes to osmotic stress. In fact, BRX was found to be an essential factor for activation of the nuclear factor of activated t-cells 5 (NFAT5) via a p38MAPK-dependent cascade with JIP4. This observation indicates that one role of BRX is to function as link to integrate osmotic stress and inflammation. In the coming year, we plan to further characterize the role of BRX in development and cancer using our murine model.

子宫肌瘤 子宫肌瘤是一种高度流行的疾病，但平滑肌瘤生长和发育的根本原因仍然知之甚少。我们过去的研究表明，纤维瘤中细胞外基质（ECM）的改变可能会影响纤维瘤的生长和发育。在过去的一年中，我们发现ATF-3的表达失调可能是机械应力和纤维瘤发展之间的联系。在另一项研究中，我们发现纤维瘤中TGF-β水平升高会导致ECM蛋白versican表达增加。同样在过去的一年里，该部门与Wood博士和Venkatesan博士合作，开始了MRI引导高频超声（HIFU）治疗子宫肌瘤的试验。此外，我们完成了一个病例系列的分析，检查子宫肌瘤切除术（切除肌瘤）可能损害卵巢功能。在接下来的一年里，我们计划更详细地剖析肌瘤中改变的机械信号，我们还计划扩大HIFU作为子宫肌瘤治疗方式的研究。 子宫内膜异位症与慢性盆腔疼痛 在过去的一年中，与Nieman博士合作，Stratton博士完成了一项雷洛昔芬治疗盆腔炎相关盆腔疼痛的研究。与预期相反，雷洛昔芬似乎加速，而不是防止盆腔疼痛的复发。在与格林和Sinaii博士的合作中，Stratton博士领导的小组还研究了1000名子宫内膜异位症妇女的疾病严重程度和患者特征之间的关系。 使用这种方法，该小组设计了一个与疼痛相关的子宫内膜异位症病变特征的模型。在接下来的一年里，该小组将完成一项关于慢性盆腔疼痛和子宫内膜异位症妇女下丘脑垂体肾上腺轴的临床研究。 接受癌症治疗的妇女和女孩的卵巢功能评估和保护 许多年轻女孩和妇女是癌症幸存者，但发现她们的生殖功能因化疗或放疗而受到不可挽回的损害。在过去的一年里，该单位测试了化疗前药物治疗的小鼠模型。该模型证实了GnRH治疗的预处理效果，其似乎通过减少预处理小鼠卵巢中的细胞凋亡而起作用。在接下来的一年里，我们计划研究GnRH拮抗剂在小鼠模型中发挥作用的机制，并在年轻女性中开展GnRH激动剂化疗前治疗的临床研究。 不孕症和生殖健康差距 我们的单位继续进行不孕症和生殖健康差距的研究。在过去的一年里，阿姆斯特朗博士是一项研究的调查员，该研究调查了13万个辅助生殖周期（ART）的生殖健康差异。这项研究支持了我们之前的工作，并揭示了非洲裔美国人和亚洲妇女活产的可能性降低。 造成这种差异的原因尚不清楚。为了鼓励对生殖健康差异的研究，阿姆斯特朗博士于2009年7月在美国国立卫生研究院主持了一次关于有色人种妇女生殖问题的会议。会议产生了新的研究和合作。在过去的一年里，我们还继续进行与循证和具有成本效益的不孕症护理有关的不孕症临床研究。我们模拟了年龄和FSH水平对辅助生殖活产婴儿成本的影响。在另一项研究中，我们检查了与年龄相关的FSH增加与35岁之前FSH增加之间的差异。在接下来的一年里，我们计划研究卵巢过度刺激综合征（OHSS）的病理生理学基础，OHSS是寻求辅助生殖技术的女性的主要危险因素。 BRX（也称为AKAP 13）在心脏发育中的作用 我们继续我们的研究，原癌基因，BRX，由我们的小组克隆（也被称为AKAP 13）和BRX基因的靶向缺失的小鼠模型的研究。在与基诺博士的合作中，过去一年的研究集中在单倍型不足小鼠的脾脏尺寸缩小上。对表型的研究发现BRX参与淋巴细胞对渗透压的反应。事实上，发现BRX是通过与JIP 4的p38 MAPK依赖性级联激活活化的t细胞核因子5（NFAT 5）的必需因子。这一观察结果表明，BRX的作用之一是作为整合渗透应激和炎症的纽带。在接下来的一年里，我们计划使用我们的小鼠模型进一步表征BRX在发育和癌症中的作用。