Imaging and treatment of endometriosis in nonhuman primates

非人灵长类动物子宫内膜异位症的影像学和治疗

基本信息

批准号：
10700030
负责人：
OV D SLAYDEN
金额：
$ 39.33万
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/10700030
关键词：
Address Affect Age Animals Archives Biological Markers Cellular Metabolic Process Child Chronic Clinical Clinical Trials Collaborations Consumption Deacetylase Diagnosis Diagnostic Dichloroacetate Diet Disease Early Diagnosis Emission-Computed Tomography Endometrial Endometrium Energy Metabolism Environment Enzymes Estrogen Receptors Estrogens Evaluation Fatty acid glycerol esters Fostering Functional disorder Future Goals Huntington Disease Image Impairment Infertility Inflammation Inflammation Mediators Inflammatory Lactic acid Laparoscopy Lesion Macaca Magnetic Resonance Imaging Malignant Neoplasms Measures Mediating Mediator Medical Metabolic Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolic dysfunction Metabolism Methods Mitochondria Modeling Molecular Monitor Monkeys Organ Ovarian Pain Peritoneal Peritoneal Fluid Polycystic Ovary Syndrome Positron-Emission Tomography Pre-Clinical Model Progesterone Progesterone Receptors Proteins Pyruvate Regulation Reporting Research Personnel Resistance Resolution Respiration Review Literature Role SIRT1 gene Sampling Schedule Serum Severities Signal Transduction Sir2-like Deacetylases Staging Steroid Receptors Testing Testosterone Therapeutic Tissues Tracer Uterus Warburg Effect Woman Work X-Ray Computed Tomography aerobic glycolysis contrast enhanced contrast imaging diagnosis standard diagnostic strategy endometriosis immune cell infiltrate improved inflammatory marker inhibitor insight longitudinal analysis metabolomics mouse model nonhuman primate novel novel strategies novel therapeutics obesogenic pyruvate dehydrogenase reproductive response sensor side effect symptom management systemic inflammatory response targeted treatment therapeutic target ultrasound western diet

项目摘要

Project 3: Imaging and treatment of endometriosis in nonhuman primates SUMMARY/ABSTRACT The overarching goal of this P01 Center is to advance our understanding of the pathophysiology of endometriosis in order to improve the diagnosis and treatment of the disease in women. Endometriosis is a painful disorder of women and nonhuman primates (NHPs) in which endometrium-like tissues form estrogen-dependent lesions outside the uterus. There is currently no cure; all approved therapies target estrogen (E2) action to manage symptoms, which is of limited use in reproductive-age women due to unwanted side effects. Macaques provide excellent preclinical models for testing novel therapies that have not been fully vetted for clinical trials. However, no reliable methods exist to detect early-stage disease in either women or monkeys, and improved diagnostic approaches are needed to evaluate new therapies. Our premise is that endometriotic cell metabolism is a novel target for improved therapies for the disease. This premise emanates, in part, from studies that have revealed that consumption of an obesogenic "western-style" diet (WSD) combined with testosterone (T) treatment increases the rate and severity of endometriosis in macaques. Furthermore, a key feature of endometriotic lesions is the presentation of chronic peritoneal inflammation. Endometrial Sirtuin 1 (SIRT1) has been reported as a biomarker of endometriosis. SIRT 1 mediates endometrial progesterone resistance associated with endometriosis-induced infertility. Moreover, SIRT1 is a protein deacetylase enzyme that functions as a metabolic sensor, regulating mitochondrial respiration and aerobic glycolysis. Increased understanding of the role of SIRT1 and other inflammatory and metabolic markers may help to identify more reliable methods of diagnosis and treatment of endometriosis. Accordingly, in Specific Aim 1, we will refine positron emission tomography- computed tomography (PET-CT) with estrogen and progesterone receptor-specific tracers. We will monitor endometriotic lesion size and abundance in macaques by PET-CT and ultrasound and compare the results with a laparoscopic examination, which is currently the "gold standard" for staging the disease. In Specific Aim 2, we will evaluate cellular mediators of inflammation, progesterone resistance, and metabolic response in serum, peritoneal fluid, endometrium, and endometrial lesions; and quantify immune cell infiltration in endometriotic lesions from macaques. We will correlate these measures with the lesion burden detected by PET-CT and laparoscopy. In Specific Aim 3, we will use the macaque endometriosis model to test the effect of inhibitors against SIRT1 (Selisistat; EX-527) and the glycolytic enzyme, pyruvate dehydrogenase (dichloroacetate; DCA). During each aim, macaque samples will be archived for future study, and relevant findings will be used to inform Project 1 (Dr. Young, PI; involving PET/MRI imaging and inflammation of the disease in women) and Project 2 (Dr. Jeong, PI; involving the role of SIRT1 in mediating progesterone resistance). This work is highly complementary to the other proposed projects and will support our long-term goal of advancing novel therapies for this debilitating disease in women.

项目3：非人灵长类动物子宫内膜异位症的成像和治疗摘要/摘要 P01 中心的首要目标是增进我们对子宫内膜异位症病理生理学的理解以提高女性疾病的诊断和治疗水平。子宫内膜异位症是一种痛苦的疾病女性和非人类灵长类动物（NHP）的子宫内膜样组织形成雌激素依赖性病变子宫外。目前尚无治愈方法；所有批准的疗法均以雌激素 (E2) 作用为目标由于不良副作用，该药物在育龄妇女中的使用有限。猕猴提供用于测试尚未经过临床试验充分审查的新疗法的优秀临床前模型。然而，不存在可靠的方法来检测女性或猴子的早期疾病，并且改进了诊断需要方法来评估新疗法。我们的前提是子宫内膜异位细胞代谢是一种新的改善该疾病治疗的目标。这一前提部分源于研究表明食用致胖的“西式”饮食 (WSD) 并结合睾酮 (T) 治疗增加猕猴子宫内膜异位症的发生率和严重程度。此外，子宫内膜异位症的一个重要特征是病变是慢性腹膜炎症的表现。子宫内膜 Sirtuin 1 (SIRT1) 已被报道作为子宫内膜异位症的生物标志物。 SIRT 1 介导子宫内膜黄体酮抵抗子宫内膜异位症引起的不孕症。此外，SIRT1 是一种蛋白质脱乙酰酶，可作为代谢酶传感器，调节线粒体呼吸和有氧糖酵解。加深对 SIRT1 作用的了解以及其他炎症和代谢标志物可能有助于确定更可靠的诊断和治疗方法子宫内膜异位症的治疗。因此，在具体目标 1 中，我们将完善正电子发射断层扫描—— 使用雌激素和孕激素受体特异性示踪剂进行计算机断层扫描 (PET-CT)。我们将监控通过 PET-CT 和超声检查猕猴子宫内膜异位病变的大小和丰度，并将结果与腹腔镜检查，这是目前疾病分期的“金标准”。在具体目标 2 中，我们将评估血清中炎症、孕激素抵抗和代谢反应的细胞介质，腹膜液、子宫内膜和子宫内膜病变；并量化子宫内膜异位症中的免疫细胞浸润来自猕猴的损伤。我们会将这些措施与 PET-CT 检测到的病变负担相关联，腹腔镜检查。在具体目标3中，我们将使用猕猴子宫内膜异位症模型来测试抑制剂的效果对抗 SIRT1（Selisistat；EX-527）和糖酵解酶丙酮酸脱氢酶（二氯乙酸盐；DCA）。在每个目标期间，猕猴样本将被存档以供未来研究，相关发现将用于提供信息项目 1（Young 博士，PI；涉及 PET/MRI 成像和女性疾病的炎症）和项目 2 （Jeong 博士，PI；涉及 SIRT1 在介导黄体酮抵抗中的作用）。这部作品的水准很高对其他拟议项目的补充，并将支持我们推进新疗法的长期目标对于这种使女性衰弱的疾病。