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: 10474484
• 负责人: OV D SLAYDEN
• 金额: $ 38.28万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474484
• 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; Uterus; Warburg Effect; Woman; Work; X-Ray Computed Tomography; aerobic glycolysis; contrast enhanced; contrast imaging; diagnosis standard; diagnostic strategy; endometriosis; 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

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 这个P01中心的首要目标是促进我们对子宫内膜异位症病理生理学的理解 以提高女性对该病的诊断和治疗水平。子宫内膜异位症是一种痛苦的疾病 女性和非人灵长类动物，子宫内膜样组织形成雌激素依赖性病变 在子宫外。目前还没有治愈方法；所有已批准的治疗方法都针对雌激素(E2)的作用来管理 症状，由于不想要的副作用，对育龄妇女的使用有限。猕猴提供 优秀的临床前模型，用于测试尚未完全经过临床试验审查的新疗法。然而， 目前还没有可靠的方法来检测妇女或猴子的早期疾病，也没有改进的诊断方法 需要一些方法来评估新的疗法。我们的前提是子宫内膜异位症细胞代谢是一种新的 目标是改进疾病的治疗方法。这一前提部分源于一项研究，该研究揭示了 将肥胖的西式饮食(WSD)与睾酮(T)治疗相结合 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关键特征 病变是慢性腹膜炎症的表现。子宫内膜Sirtuin 1(SIRT1)已有报道 作为子宫内膜异位症的生物标志物。Sirt-1介导子宫内膜孕酮抵抗与 子宫内膜异位症致不孕症。此外，SIRT1是一种蛋白质脱乙酰基酶，其功能是代谢 传感器，调节线粒体呼吸和有氧糖酵解。加深对SIRT1作用的理解 和其他炎症和代谢标志物可能有助于确定更可靠的诊断和 治疗子宫内膜异位症。因此，在具体目标1中，我们将改进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的计算机断层扫描(PET-CT)。我们会监控 用PET-CT和超声检测猕猴子宫内膜异位症病变的大小和丰度，并与 腹腔镜检查，这是目前诊断疾病的“黄金标准”。在具体目标2中， 我们将评估炎症、黄体酮抵抗和血清代谢反应的细胞介质， 腹腔液、子宫内膜和子宫内膜病变；并对子宫内膜异位症中免疫细胞的渗透进行定量 猕猴造成的损伤。我们将把这些措施与PET-CT和 腹腔镜。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。 抗SIRT1(Selisistat；ex-527)和糖酵解酶丙酮酸脱氢酶(二氯乙酸酯；DCA)。 在每个目标期间，猕猴样本将被存档以供将来研究，相关发现将被用来提供信息 项目1(Young博士，Pi；涉及PET/MRI成像和妇女的疾病炎症)和项目2 (Jeong博士，Pi；涉及SIRT1在调节孕酮抵抗中的作用)。这项工作具有很高的 与其他拟议项目相辅相成，并将支持我们推进新疗法的长期目标 治疗这种使女性衰弱的疾病。