Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis

合作中心开发改进的子宫内膜异位症诊断和治疗方法

基本信息

批准号：
10700014
负责人：
STEVEN L YOUNG
金额：
$ 139.44万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700014
关键词：
Affect Animal Model Awareness Bioinformatics Cell Proliferation Chronic Clinical Clinical Research Collaborations Data Detection Development Diagnosis Diagnostic Diagnostic Imaging Disease Dysmenorrhea Early Diagnosis Early treatment Education Education and Outreach Endometrial Energy Metabolism Engineering Epigenetic Process Epithelium Estrogen Receptors Evaluation Functional disorder Future Genomics Goals Growth HDAC4 gene Health Health Benefit Heart Human Image Imaging Techniques In Vitro Infertility Inflammation Inflammation Mediators Inflammatory Intervention Knowledge Lesion Macaca mulatta Metabolic Methods Modeling Molecular Molecular Target Monkeys Mus Operative Surgical Procedures Pain Patients Personal Satisfaction Play Post-Translational Protein Processing Process Progesterone Progesterone Receptors Proteins Provider Research Personnel Resistance Resolution Role SIRT1 gene Scientist Signal Transduction Stigmatization System Testing Testosterone Therapeutic Tissues Uterus Woman care providers chronic pelvic pain college community setting comparative comparative genomics data integration design endometriosis high school human data imaging modality implantation improved in vitro Model innovation insight lipid mediator non-invasive imaging nonhuman primate noninvasive diagnosis novel overexpression pre-clinical prevent protein function receptor expression synergism therapeutic target tool western diet young woman

项目摘要

Collaborative Center to Develop Improved Diagnostic and Therapeutic Approaches to Endometriosis ABSTRACT The overarching goal of this Center is to develop advanced tools and insights for improved understanding of the pathophysiology of endometriosis, a disease in which endometrial tissue grows outside the uterus and can cause severe dysmenorrhea, pain, infertility and other sequelae. We pursue this goal to enhance the diagnosis, assessment, and treatment of women suffering from this common and devastating disease. A clear pathophysiologic understanding of endometriosis has been difficult to achieve due, in part, to the reliance on surgery for diagnosis and lesion assessment. Reliance on surgery delays diagnosis and prevents frequent or repeated evaluation. In recent years, however, collaborations between scientists in our team have advanced a unifying pathophysiological principle--that of progesterone resistance. Most other pathophysiological features of endometriosis, including persistent epithelial estrogen receptor action, persistent estrogen receptor and progesterone receptor expression, cellular proliferation, inflammation, pain, and infertility, can be ascribed to progesterone resistance. Recently, important findings by this consortium show that Sirtuin 1 (SIRT1), an epigenetic modulator, can cause progesterone resistance, resulting in exacerbation of downstream effects. SIRT1 is a histone deacetylase that also directly regulates the function of proteins directing inflammatory and metabolic signaling. We find consistent overexpression of endometrial SIRT1 across all species that we have tested, including humans, non-human primates, and mice, highlighting a likely central role for SIRT1 in endometriosis pathophysiology. Furthermore, preliminary studies indicate that SIRT1 overexpression plays a direct role in lesion survival as well as infertility and has a potential role as a therapeutic target. We present three key projects based on our burgeoning pathophysiological data to deepen our knowledge, catalyze the development of novel, non-invasive diagnostic and assessment methods and promote non-hormonal therapeutic options for affected women. The impact of these three projects on women will be enhanced by patient and provider educational initiatives from the Endometriosis Outreach and Education (EOE) Core and deep integration of synergistic data from human, non-human primate, mouse, and in vitro systems, enhanced by the Comparative Genomics and Bioinformatics (CGB) Core. Collectively, the projects and cores contribute to three synergistic aims: 1) Enhance early diagnosis and assessment of endometriosis lesions by developing non-invasive imaging techniques and promoting public awareness; 2) Determine inflammatory and metabolic changes that underlie the disease process; and 3) Develop new molecular targets for non-hormonal, non-surgical treatments for endometriosis; The successful completion of these aims will lead to a long-lasting improvement in the lives of women suffering from endometriosis.

协作中心，以开发改进子宫内膜异位症的诊断和治疗方法抽象的该中心的总体目标是开发先进的工具和见解，以提高理解子宫内膜异位症的病理生理学，一种子宫内膜组织在子宫外生长和会引起严重的痛经，疼痛，不育和其他后遗症。我们追求这个目标来增强患有这种常见和毁灭性疾病的妇女的诊断，评估和治疗。清晰对子宫内膜异位症的病理生理理解很难在部分地依赖于依赖诊断和病变评估的手术。依靠手术延迟诊断，并防止经常或重复评估。然而，近年来，我们团队中科学家之间的合作提高了统一的病理生理原理 - 孕酮耐药性。大多数其他病理生理特征子宫内膜异位症，包括持续的上皮雌激素受体作用，持续性雌激素受体和孕酮受体表达，细胞增殖，炎症，疼痛和不育可以归因于孕酮耐药性。最近，该财团的重要发现表明Sirtuin 1（Sirt1），一个表观遗传调节剂会引起孕酮耐药性，从而导致下游效应加剧。 SIRT1是一种组蛋白脱乙酰基酶，它也直接调节引导炎症和的蛋白质功能代谢信号传导。我们发现在所有具有的物种中，子宫内膜SIRT1的过表达一致经过测试，包括人类，非人类灵长类动物和小鼠，突出了SIRT1在子宫内膜异位病理生理学。此外，初步研究表明SIRT1过表达扮演在病变生存和不孕症中的直接作用，并且具有治疗靶标的潜在作用。我们提出三个基于我们新兴的病理生理数据的关键项目，以加深我们的知识，催化开发新型，非侵入性诊断和评估方法，并促进非激素治疗受影响妇女的选择。这三个项目对妇女的影响将由患者加强，子宫内膜异位外展和教育（EOE）核心和深度整合的提供者教育计划来自人类，非人类灵长类动物，小鼠和体外系统的协同数据，通过比较增强基因组学和生物信息学（CGB）核心。总体而言，项目和核心有助于三个协同作用目的：1）通过开发非侵入性增强子宫内膜异位病变的早期诊断和评估成像技术并提高公众意识； 2）确定炎症和代谢变化这是疾病过程的基础； 3）开发非荷尔蒙的新分子靶标子宫内膜异位症治疗；这些目标的成功完成将导致持久的改进在患有子宫内膜异位症的妇女的生活中。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Defining recurrent implantation failure: a profusion of confusion or simply an illusion?

DOI：
10.1016/j.fertnstert.2021.10.023
发表时间：
2021-12
期刊：
Fertility and sterility
影响因子：
6.7
作者：
Garneau AS;Young SL
通讯作者：
Young SL

Corrigendum to: Role of SIRT1 and Progesterone Resistance in Normal and Abnormal Endometrium.

勘误表：SIRT1 和孕酮抵抗在正常和异常子宫内膜中的作用。

DOI：
10.1210/clinem/dgab880
发表时间：
2022
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
通讯作者：

Progesterone Signaling in Endometrial Epithelial Organoids.

DOI：
10.3390/cells11111760
发表时间：
2022-05-27
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology.

DOI：
10.3389/fimmu.2022.961599
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Effects of acute estradiol and progesterone on perimenstrual exacerbation of suicidal ideation and related symptoms: a crossover randomized controlled trial.

DOI：
10.1038/s41398-022-02294-1
发表时间：
2022-12-30
期刊：
TRANSLATIONAL PSYCHIATRY
影响因子：
6.8
作者：
Eisenlohr-Moul, Tory A.;Bowers, Savannah M.;Prinstein, Mitchell J.;Schmalenberger, Katja M.;Walsh, Erin C.;Young, Steven L.;Rubinow, David R.;Girdler, Susan S.
通讯作者：
Girdler, Susan S.