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 总结/摘要 P01中心的首要目标是提高我们对子宫内膜异位症病理生理学的认识 以提高对妇女疾病的诊断和治疗。子宫内膜异位症是一种痛苦的疾病， 子宫内膜样组织形成雌激素依赖性病变的女性和非人灵长类动物（NHP） 在子宫外。目前还没有治愈方法;所有批准的治疗方法都以雌激素（E2）作用为目标， 症状，这是有限的使用在育龄妇女由于不必要的副作用。猕猴提供 用于测试尚未完全通过临床试验审查的新疗法的出色临床前模型。然而，在这方面， 目前还没有可靠的方法来检测妇女或猴子的早期疾病， 需要评估新疗法的方法。我们的前提是，细胞代谢是一种新的 改善疾病治疗的目标。这一前提部分来自于一些研究， 食用肥胖的“西式”饮食（WSD）结合睾酮（T）治疗， 增加猕猴子宫内膜异位症的发病率和严重程度。此外，一个关键的特点， 病变是慢性腹膜炎症的表现。子宫内膜Sirtuin 1（SIRT 1） 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， 子宫内膜异位症导致的不孕症此外，SIRT 1是一种蛋白质脱乙酰酶，其作为代谢酶发挥作用。 传感器，调节线粒体呼吸和有氧糖酵解。增加对SIRT作用的了解1 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方法， 子宫内膜异位症的治疗因此，在具体目标1中，我们将改进正电子发射断层扫描- 计算机断层扫描（PET-CT）与雌激素和孕激素受体特异性示踪剂。我们会监察 通过PET-CT和超声检测猕猴中增生性病变的大小和丰度，并将结果与 腹腔镜检查，这是目前的“黄金标准”分期的疾病。在具体目标2中， 我们将评估炎症、孕酮抵抗和血清中代谢反应的细胞介质， 腹膜液，子宫内膜和子宫内膜病变;并量化免疫细胞浸润， 猕猴的病变我们将这些测量与PET-CT检测到的病变负荷相关联， 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作用。 针对SIRT 1（Selisistat; EX-527）和糖酵解酶丙酮酸脱氢酶（二氯乙酸; DCA）。 在每个目标期间，猕猴样本将被存档以供未来研究，相关发现将用于告知 项目1（Young博士，PI;涉及PET/MRI成像和女性疾病炎症）和项目2 (Dr. Jeong，PI;涉及SIRT 1在介导孕酮抗性中的作用）。这项工作是高度 与其他拟议项目相辅相成，并将支持我们推进新型疗法的长期目标 这种使女性衰弱的疾病。