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

• 批准号: 10309094
• 负责人: OV D SLAYDEN
• 金额: $ 39.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10309094
• 关键词: Address; Affect; Age; Animals; Archives; Biological Markers; Cells; Cellular Metabolic Process; Child; Chronic; Clinical; Clinical Trials; Collaborations; Consumption; Deacetylase; Diagnosis; Diagnostic; Dichloroacetate; Diet; Disease; Emission-Computed Tomography; Endometrial; Endometrium; Energy Metabolism; Environment; Enzymes; Estrogen Receptors; Estrogens; Evaluation; Fatty acid glycerol esters; Fostering; Functional disorder; Future; Goals; Gold; Huntington Disease; Image; Immune; Impairment; Infertility; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Lactic acid; Laparoscopy; Lesion; Macaca; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; 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; Ultrasonography; Uterus; Warburg Effect; Woman; Work; X-Ray Computed Tomography; aerobic glycolysis; contrast enhanced; contrast imaging; diagnosis standard; endometriosis; improved; inflammatory marker; inhibitor/antagonist; 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; western diet

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：非人类灵长类动物子宫内膜异位症的成像和治疗 摘要/摘要 这个P01中心的总体目标是提高我们对子宫内膜异位症病理生理的理解 为了改善女性疾病的诊断和治疗。子宫内膜异位症是一种疼痛疾病 女性和非人类灵长类动物（NHP），其中子宫内膜样组织形成雌激素依赖性病变 子宫外。目前无法治愈；所有批准的疗法目标雌激素（E2）行动 由于不需要的副作用，症状在生殖时代女性中的使用有限。猕猴提供 尚未完全审查用于临床试验的新型疗法的出色临床前模型。然而， 尚无可靠的方法来检测女性或猴子的早期疾病，并改善了诊断 需要方法来评估新疗法。我们的前提是子宫内膜细胞代谢是一种新颖 改善该疾病疗法的靶标。这个前提的部分是从揭示的研究中发出的 肥胖的“西方风格”饮食（WSD）与睾丸激素（T）治疗的消费量 增加了猕猴中子宫内膜异位症的速度和严重程度。此外，子宫内膜含量的关键特征 病变是慢性腹膜炎症的表现。据报道，子宫内膜SIRTUIN 1（SIRT1） 作为子宫内膜异位症的生物标志物。 SIRT 1介导与子宫内膜孕酮抗性 子宫内膜异位症引起的不育症。此外，SIRT1是一种蛋白质脱乙酰基酶，可作为代谢 传感器，调节线粒体呼吸和有氧糖酵解。对SIRT的作用的了解增加了 其他炎症和代谢标记物可能有助于确定更可靠的诊断方法 子宫内膜异位症的治疗。因此，在特定的目标1中，我们将完善正电子发射断层扫描 - 带有雌激素和孕酮受体特异性示踪剂的计算机断层扫描（PET-CT）。我们将监视 子宫内膜病变的大小和PET-CT猕猴的丰度和超声检查，并将结果与​​结果进行比较 腹腔镜检查，目前是分期疾病的“黄金标准”。在特定的目标2中， 我们将评估血清中炎症，孕酮耐药性和代谢反应的细胞介质， 腹膜液，子宫内膜和子宫内膜病变；并量化子宫内膜含量的免疫细胞浸润 猕猴的病变。我们将将这些措施与PET-CT检测到的病变负担相关联 腹腔镜检查。在特定目标3中，我们将使用猕猴子宫内膜异位症模型测试抑制剂的效果 针对SIRT1（SELISISTAT； EX-527）和糖酵解酶，丙酮酸脱氢酶（二氯乙酸； DCA）。 在每个目标中，猕猴样品将被存档以进行未来研究，相关发现将用于告知 项目1（Young博士，PI；涉及妇女疾病的PET/MRI成像和疾病的炎症）和项目2 （Jeong博士，PI；涉及SIRT1在介导孕酮耐药性中的作用）。这项工作很高 补充其他提议的项目，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。